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Tumor-infiltrating lymphocytes in the immunotherapy era

Cellular & Molecular Immunology volume 18, pages 842–859 (2021)Cite this article

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Abstract

The clinical success of cancer immune checkpoint blockade (ICB) has refocused attention on tumor-infiltrating lymphocytes (TILs) across cancer types. The outcome of immune checkpoint inhibitor therapy in cancer patients has been linked to the quality and magnitude of T cell, NK cell, and more recently, B cell responses within the tumor microenvironment. State-of-the-art single-cell analysis of TIL gene expression profiles and clonality has revealed a remarkable degree of cellular heterogeneity and distinct patterns of immune activation and exhaustion. Many of these states are conserved across tumor types, in line with the broad responses observed clinically. Despite this homology, not all cancer types with similar TIL landscapes respond similarly to immunotherapy, highlighting the complexity of the underlying tumor-immune interactions. This observation is further confounded by the strong prognostic benefit of TILs observed for tumor types that have so far respond poorly to immunotherapy. Thus, while a holistic view of lymphocyte infiltration and dysfunction on a single-cell level is emerging, the search for response and prognostic biomarkers is just beginning. Within this review, we discuss recent advances in the understanding of TIL biology, their prognostic benefit, and their predictive value for therapy.

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References

  1. Zloza, A. & Al-Harthi, L. Multiple populations of T lymphocytes are distinguished by the level of CD4 and CD8 coexpression and require individual consideration. J. Leukoc. Biol. 79, 4–6 (2006).

    Article  PubMed  CAS  Google Scholar 

  2. Parrot, T. et al. Transcriptomic features of tumour-infiltrating CD4lowCD8high double positive αβ T cells in melanoma. Sci Rep. 10, 5900 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Menard, L. C. et al. Renal cell carcinoma (RCC) tumors display large expansion of double positive (DP) CD4+CD8+ T cells with expression of exhaustion markers. Front Immunol. 9, 2728 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Bohner, P. et al. Double positive CD4+CD8+ T cells are enriched in urological cancers and favor T helper-2 polarization. Front Immunol. 10, 622 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Desfrançois, J. et al. Double positive CD4CD8 αβ T cells: a new tumor-reactive population in human melanomas. PLoS One. 5, e8437 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Desfrançois, J. et al. Increased frequency of nonconventional double positive CD4CD8 αβ T cells in human breast pleural effusions. Int J. Cancer 125, 374–380 (2009).

    Article  PubMed  CAS  Google Scholar 

  7. Fischer, K. et al. Isolation and characterization of human antigen-specific TCRαβ+ CD4-CD8- double-negative regulatory T cells. Blood 105, 2828–2835 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Priatel, J. J., Utting, O. & Teh, H.-S. TCR/self-antigen interactions drive double-negative T cell peripheral expansion and differentiation into suppressor cells. J. Immunol. 167, 6188–6194 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Lee, J. B. et al. Developing allogeneic double-negative T cells as a novel off-the-shelf adoptive cellular therapy for cancer. Clin. Cancer Res. 25, 2241–2253 (2019).

    Article  CAS  PubMed  Google Scholar 

  10. Greenplate, A. R. et al. Computational immune monitoring reveals abnormal double-negative T cells present across human tumor types. Cancer Immunol. Res. 7, 86–99 (2019).

    Article  CAS  PubMed  Google Scholar 

  11. Hamann, D. et al. Phenotypic and functional separation of memory and effector human CD8+ T cells. J. Exp. Med. 186, 1407–CD18 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gattinoni, L. et al. T memory stem cells in health and disease. Nat Med. 23, 18–27 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Egelston, C. A. et al. Human breast tumor-infiltrating CD8+ T cells retain polyfunctionality despite PD-1 expression. Nat Commun. 9, 4297 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Gattinoni, L. et al. A human memory T cell subset with stem cell-like properties. Nat. Med 17, 1290–1297 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Romero, P. et al. Four functionally distinct populations of human effector-memory CD8+ T lymphocytes. J. Immunol. 178, 4112–4119 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Pagès, F. et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N. Engl. J. Med 353, 2654–2666 (2005).

    Article  PubMed  Google Scholar 

  17. Klebanoff, C. A. et al. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc. Natl Acad. Sci. USA 102, 9571–9576 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ahmadvand, S. et al. Importance of CD45RO+ tumor-infiltrating lymphocytes in post-operative survival of breast cancer patients. Cell Oncol. 42, 343–356 (2019).

    Article  CAS  Google Scholar 

  19. Cheuk, S. et al. CD49a expression defines tissue-resident CD8+ T cells poised for cytotoxic function in human skin. Immunity 46, 287–300 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zaid, A. et al. Chemokine receptor–dependent control of skin tissue–resident memory T cell formation. J. Immunol. 199, 2451–2459 (2017).

    Article  CAS  PubMed  Google Scholar 

  21. Oja, A. E. et al. Functional heterogeneity of CD4+ tumor-infiltrating lymphocytes with a resident memory phenotype in NSCLC. Front Immunol. 9, 2654 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Kim, Y., Shin, Y. & Kang, G. H. Prognostic significance of CD103+ immune cells in solid tumor: a systemic review and meta-analysis. Sci. Rep. 9, 1–7 (2019).

    Google Scholar 

  23. Solomon, B. et al. Identification of an excellent prognosis subset of human papillomavirus-associated oropharyngeal cancer patients by quantification of intratumoral CD103+ immune cell abundance. Ann. Oncol. Off J. Eur. Soc. Med. Oncol. 30, 1638–1646 (2019).

    Article  CAS  Google Scholar 

  24. Mann, J. E. et al. Analysis of tumor-infiltrating CD103 resident memory T-cell content in recurrent laryngeal squamous cell carcinoma. Cancer Immunol. Immunother. 68, 213–20. (2019).

    Article  CAS  PubMed  Google Scholar 

  25. Hu, W., Sun, R., Chen, L., Zheng, X. & Jiang, J. Prognostic significance of resident CD103+CD8+T cells in human colorectal cancer tissues. Acta Histochem. 121, 657–663 (2019).

    Article  CAS  PubMed  Google Scholar 

  26. Edwards, J. et al. CD103+ tumor-resident CD8+ T cells are associated with improved survival in immunotherapy-naïve melanoma patients and expand significantly during anti-PD-1 treatment. Clin. Cancer Res. 24, 3036–3045 (2018).

    Article  CAS  PubMed  Google Scholar 

  27. Shields, B. D. et al. Loss of E-cadherin inhibits CD103 antitumor activity and reduces checkpoint blockade responsiveness in melanoma. Cancer Res. 79, 1113–1123 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Duhen, T. et al. Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nat. Commun. 9, 1–13 (2018).

    Article  CAS  Google Scholar 

  29. Simoni, Y. et al. Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 557, 575–579 (2018).

    Article  CAS  PubMed  Google Scholar 

  30. Rosato P. C., et al. Virus-specific memory T cells populate tumors and can be repurposed for tumor immunotherapy. https://doi.org/10.1038/s41467-019-08534-1.

  31. Liu, D. et al. Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma. Nat. Med. 25, 1916–1927 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Alspach, E. et al. MHC-II neoantigens shape tumour immunity and response to immunotherapy. Nature 574, 696–701 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Marty, R., Thompson, W. K., Salem, R. M., Zanetti, M. & Carter, H. Evolutionary pressure against MHC class II binding cancer mutations. Cell 175, 416–428.e13 (2018).

    Article  CAS  Google Scholar 

  34. Borst, J., Ahrends, T., Bąbała, N., Melief, C. J. M. & Kastenmüller, W. CD4+ T cell help in cancer immunology and immunotherapy. Nat. Rev. Immunol. 18, 635–647 (2018).

    Article  CAS  PubMed  Google Scholar 

  35. Bevan, M. J. Helping the CD8+ T-cell response. Nat. Rev. Immunol. 4, 595–602 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Qiu, L. et al. Functionally impaired follicular helper T cells induce regulatory B cells and CD14+ human leukocyte antigen-DR− cell differentiation in non-small cell lung cancer. Cancer Sci. 109, 3751–3761 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Crotty, S. T. Follicular helper cell biology: a decade of discovery and diseases. Immunity 50, 1132–1148 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Qin L., et al. Insights into the molecular mechanisms of T follicular helper-mediated immunity and pathology. Front Immunol. 9. https://doi.org/10.3389/fimmu.2018.01884/full (2018).

  39. Kumar, P., Bhattacharya, P. & Prabhakar, B. S. A comprehensive review on the role of co-signaling receptors and Treg homeostasis in autoimmunity and tumor immunity. J. Autoimmun. 95, 77–99 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10, 942–949 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Hiraoka, N., Onozato, K., Kosuge, T. & Hirohashi, S. Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin. Cancer Res. 12, 5423–5434 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Perrone, G. et al. Intratumoural FOXP3-positive regulatory T cells are associated with adverse prognosis in radically resected gastric cancer. Eur. J. Cancer 44, 1875–1882 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Jordanova, E. S. et al. Human leukocyte antigen class I, MHC class I chain-related molecule A, and CD8+/regulatory T-cell ratio: Which variable determines survival of cervical cancer patients? Clin. Cancer Res. 14, 2028–2035 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Bates, G. J. et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J. Clin. Oncol. 24, 5373–5380 (2006).

    Article  PubMed  Google Scholar 

  45. Sinicrope, F. A. et al. Intraepithelial effector (CD3+)/regulatory (FoxP3+) T-cell ratio predicts a clinical outcome of human colon carcinoma. Gastroenterology 137, 1270–1279 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Sawant, D. V. et al. Adaptive plasticity of IL-10+ and IL-35+ Treg cells cooperatively promotes tumor T cell exhaustion. Nat. Immunol. 20, 724–735 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Qureshi, O. S. et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332, 600–603 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Liu, Z. et al. Novel effector phenotype of TIM-3þ Regulatory T cells leads to enhanced suppressive function in head and neck cancer patients. Clin. Cancer Res. 24, 4529–4538 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Overacre-Delgoffe, A. E. et al. Interferon-γ drives treg fragility to promote anti-tumor immunity. Cell 169, 1130–1141.e11 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Fridman, W. H., Zitvogel, L., Sautès-Fridman, C. & Kroemer, G. The immune contexture in cancer prognosis and treatment. Nat. Rev. Clin. Oncol. 14, 717–734 (2017).

    Article  CAS  PubMed  Google Scholar 

  51. Morrow E. S., Roseweir A., Edwards J. The role of gamma delta T lymphocytes in breast cancer: a review. Transl. Res. 203, 88–96 (2019).

  52. Xiang Z., Tu W. Dual face of Vγ9Vdδ2-T cells in tumor immunology: Anti- versus pro-tumoral activities. Front. Immunol. 8, 1041 (2017).

  53. Künkele, K.-P. et al. Vγ9Vδ2 T cells: can we re-purpose a potent anti-infection mechanism for cancer therapy? Cells 9, 829 (2020).

    Article  PubMed Central  CAS  Google Scholar 

  54. Rezende, R. M. et al. γδ T cells control humoral immune response by inducing T follicular helper cell differentiation. Nat Commun. 9, 3151 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Caccamo, N. et al. IL-21 regulates the differentiation of a human γδ T cell subset equipped with B cell helper activity. PLoS One. 7, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223172 (2012).

  56. Peters, C. et al. TGF-β enhances the cytotoxic activity of Vδ2 T cells. Oncoimmunology. 8, e1522471 (2019).

    Article  PubMed  Google Scholar 

  57. Miller, B. C. et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol. 20, 326–336 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Siddiqui, I. et al. Intratumoral Tcf1 + PD-1 + CD8 + T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 50, 195–211.e10 (2019).

    Article  CAS  PubMed  Google Scholar 

  59. Martinez-Usatorre, A. et al. Enhanced phenotype definition for precision isolation of precursor exhausted tumor-infiltrating CD8 T cells. Front Immunol. 11, 340 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Sade-Feldman, M. et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 175, 998–1013.e20 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Brummelman, J. et al. High-dimensional single cell analysis identifies stem-like cytotoxic CD8+ T cells infiltrating human tumors. J. Exp. Med. 215, 2520–2535 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. He, R. et al. Follicular CXCR5-expressing CD8+ T cells curtail chronic viral infection. Nature 537, 412–416 (2016).

    Article  CAS  PubMed  Google Scholar 

  63. Guo, X. et al. Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing. Nat. Med. 24, 978–985 (2018).

    Article  CAS  PubMed  Google Scholar 

  64. Yamauchi, T. et al. CX3CR1–CD8+ T cells are critical in antitumor efficacy but functionally suppressed in the tumor microenvironment. JCI Insight. 5, e133920 (2020).

    Article  PubMed Central  Google Scholar 

  65. Khan, O. et al. TOX transcriptionally and epigenetically programs CD8 + T cell exhaustion. Nature 571, 211–218 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Scott, A. C. et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature 571, 270–274 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Mann, T. H. & Kaech, S. M. Tick-TOX, it’s time for T cell exhaustion. Nat. Immunol. 20, 1092–1094 (2019).

    Article  CAS  PubMed  Google Scholar 

  68. Canale, F. P. et al. CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells. Cancer Res. 78, 115–128 (2018).

    Article  CAS  PubMed  Google Scholar 

  69. Webb, J. R., Milne, K. & Nelson, B. H. PD-1 and CD103 are widely coexpressed on prognostically favorable intraepithelial CD8 T cells in human ovarian cancer. Cancer Immunol. Res. 3, 926–935 (2015).

    Article  CAS  PubMed  Google Scholar 

  70. Djenidi, F. et al. CD8 + CD103 + tumor–infiltrating lymphocytes are tumor-specific tissue-resident memory T cells and a prognostic factor for survival in lung cancer patients. J. Immunol. 194, 3475–3486 (2015).

    Article  CAS  PubMed  Google Scholar 

  71. Ganesan, A. P. et al. Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer. Nat. Immunol. 18, 940–950 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Berntsson, J., Nodin, B., Eberhard, J., Micke, P. & Jirström, K. Prognostic impact of tumour-infiltrating B cells and plasma cells in colorectal cancer. Int J. Cancer 139, 1129–1139 (2016).

    Article  CAS  PubMed  Google Scholar 

  73. Cillo, A. R. et al. Immune landscape of viral- and carcinogen-driven head and neck cancer. Immunity 52, 183–199.e9 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Garaud, S. et al. Tumor-infiltrating B cells signal functional humoral immune responses in breast cancer. JCI Insight 4, 1–20 (2019).

    Article  Google Scholar 

  75. Helmink, B. A. et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577, 549–555 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Shi, J. Y. et al. Margin-infiltrating CD20+ B cells display an atypical memory phenotype and correlate with favorable prognosis in hepatocellular carcinoma. Clin. Cancer Res. 19, 5994–6005 (2013).

    Article  CAS  PubMed  Google Scholar 

  77. Shalapour, S. et al. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature 521, 94–98 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wei, X. et al. Regulatory B cells contribute to the impaired antitumor immunity in ovarian cancer patients. Tumor Biol. 37, 6581–6588 (2016).

    Article  CAS  Google Scholar 

  79. Xiao, X. et al. PD-1hi identifies a novel regulatory b-cell population in human hepatoma that promotes disease progression. Cancer Discov. 6, 546–559 (2016).

    Article  CAS  PubMed  Google Scholar 

  80. Zhou, X., Su, Y. X., Lao, X. M., Liang, Y. J. & Liao, G. Q. CD19+IL-10+ regulatory B cells affect survival of tongue squamous cell carcinoma patients and induce resting CD4+ T cells to CD4+Foxp3+ regulatory T cells. Oral. Oncol. 53, 27–35 (2016).

    Article  CAS  PubMed  Google Scholar 

  81. Dieu-Nosjean, M.-C. et al. Tertiary lymphoid structures, drivers of the anti-tumor responses in human cancers. Immunol. Rev. 271, 260–275 (2016).

    Article  CAS  PubMed  Google Scholar 

  82. Sautès-Fridman C., Petitprez F., Calderaro J., Fridman W. H. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat. Rev. Cancer 19, 307–325 (2019).

  83. Hu, X. et al. Landscape of B cell immunity and related immune evasion in human cancers. Nat. Genet 51, 1068 (2019).

    Article  CAS  PubMed  Google Scholar 

  84. Wouters M. C. A., Nelson B. H. Prognostic significance of tumor-infiltrating B cells and plasma cells in human cancer. Clin. Cancer Res. 24, 6125–6135. http://www.ncbi.nlm.nih.gov/pubmed/30049748 (2018).

  85. Ana, M., Avalos, H. L. P. Early BCR events and antigen capture, processing, and loading on MHC class II on B Cells. Front Immunol. 5, 92 (2014).

    Google Scholar 

  86. Hua, Z. & Hou, B. The role of B cell antigen presentation in the initiation of CD4 + T cell response. Immunol. Rev. 296, 1–12 (2020).

    Article  CAS  Google Scholar 

  87. Hong, S. et al. B cells are the dominant antigen-presenting cells that activate naive CD4+ T cells upon immunization with a virus-derived nanoparticle antigen. Immunity 49, 695–708.e4 (2018).

    Article  CAS  PubMed  Google Scholar 

  88. Bruno, T. C. et al. Antigen-presenting intratumoral B cells affect CD4+ TIL phenotypes in non–small cell lung cancer patients. Cancer Immunol. Res. 5, 898–907 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Jones H., Wang Y., Aldridge B., Archive J. W.-C. I. Lung and splenic B cells facilitate diverse effects on in vitro measures of antitumor immune responses. AACR. https://cancerimmunolres.aacrjournals.org/content/canimmarch/8/1/4.short (2008).

  90. Kroeger, D. R., Milne, K. & Nelson, B. H. Tumor-infiltrating plasma cells are associated with tertiary lymphoid structures, cytolytic T-cell responses, and superior prognosis in ovarian cancer. Clin. Cancer Res. 22, 3005–3015 (2016).

    Article  CAS  PubMed  Google Scholar 

  91. Andreu, P. et al. FcRγ activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 17, 121–134 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Mauri, C. & Bosma, A. Immune regulatory function of B cells. Annu Rev. Immunol. 30, 221–241 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. Cai X., Zhang L., Wei W. Regulatory B cells in inflammatory diseases and tumor. Int. Immunopharmacol. 67, 281–286 (2019).

  94. Madan, R. et al. Nonredundant roles for B cell-derived IL-10 in immune counter-regulation. J. Immunol. 183, 2312–2320 (2009).

    Article  CAS  PubMed  Google Scholar 

  95. Yang X., et al. T follicular helper cells and regulatory B cells dynamics in systemic lupus erythematosus. PLoS One. 9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3925141/ (2014)

  96. Daien, C. I. et al. Regulatory B10 cells are decreased in patients with rheumatoid arthritis and are inversely correlated with disease activity. Arthritis Rheumatol. 66, 2037–2046 (2014).

    Article  CAS  PubMed  Google Scholar 

  97. Lee-Chang, C. et al. Myeloid-derived suppressive cells promote B cell-mediated immunosuppression via transfer of PD-L1 in glioblastoma. Cancer. Immunol. Res. 7, 1928–1943 (2019).

    CAS  Google Scholar 

  98. Olkhanud, P. B. et al. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4+ T cells to T-regulatory cells. Cancer Res. 71, 3505–3515 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Wang, W. et al. CD19+CD24hiCD38hi Bregs involved in downregulate helper T cells and upregulate regulatory T cells in gastric cancer. Oncotarget 6, 33486–33499 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Du Y., Wei Y. Therapeutic potential of natural killer cells in gastric cancer. Front. Immunol. 10, 3095 (2019).

  101. Angka, L. et al. Natural killer cell IFNγ secretion is profoundly suppressed following colorectal cancer surgery. Ann. Surg. Oncol. 25, 3747–3754 (2018).

    Article  PubMed  Google Scholar 

  102. Hoogstad-Van Evert J. S., et al. Harnessing natural killer cells for the treatment of ovarian cancer. https://doi.org/10.1016/j.ygyno.2020.03.020 (2020).

  103. Martín-Fontecha, A. et al. Induced recruitment of NK cells to lymph nodes provides IFN-γ for TH1 priming. Nat. Immunol. 5, 1260–1265 (2004).

    Article  PubMed  CAS  Google Scholar 

  104. Böttcher, J. P. et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172, 1022–1037.e14 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Cui, F., Qu, D., Sun, R., Nan, K. Circulating CD16+CD56+ nature killer cells indicate the prognosis of colorectal cancer after initial chemotherapy. Med Oncol. 36, 84 (2019).

    Article  PubMed  CAS  Google Scholar 

  106. Peng, L. S. et al. Tumor-associated monocytes/macrophages impair NK-cell function via TGFβ1 in human gastric cancer. Cancer Immunol. Res 5, 248–256 (2017).

    Article  CAS  PubMed  Google Scholar 

  107. Vivier, E. et al. Innate Lymphoid Cells: 10 Years On. Cell 174, 1054–1066 (2018).

  108. Cortez, V. S., Colonna, M. Diversity and function of group 1 innate lymphoid cells. Immunol. Lett. 179, 19–24 (2016).

  109. Gao, Y. et al. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Nat. Immunol. 18, 1004–1015 (2017).

    Article  CAS  PubMed  Google Scholar 

  110. Cortez, V. S. et al. SMAD4 impedes the conversion of NK cells into ILC1-like cells by curtailing non-canonical TGF-β signaling. Nat. Immunol. 18 995–1003 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Hawke, L. G., Mitchell, B. Z. & Ormiston, M. L. TGF-β and IL-15 synergize through MAPK pathways to drive the conversion of human NK cells to an innate lymphoid cell 1–like phenotype. J. Immunol. 24, ji1900866 (2020).

    Google Scholar 

  112. Ercolano, G. et al. Immunosuppressive mediators impair proinflammatory innate lymphoid cell function in human malignant melanoma. Cancer Immunol Res. http://www.ncbi.nlm.nih.gov/pubmed/32019778 (2020).

  113. Moral, J. A. et al. ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity. Nature 579, 130–135 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Demaria, O. & Vivier, E. Immuno-oncology beyond TILs: unleashing TILCs. Cancer Cell 37, 428–430 (2020).

    Article  CAS  PubMed  Google Scholar 

  115. Saranchova, I. et al. Type 2 innate lymphocytes actuate immunity against tumours and limit cancer metastasis. Sci. Rep. 8, 1–17 (2018).

    Article  CAS  Google Scholar 

  116. Trabanelli, S. et al. Tumour-derived PGD2 and NKp30-B7H6 engagement drives an immunosuppressive ILC2-MDSC axis. Nat. Commun. 8, 1–14 (2017).

    Article  CAS  Google Scholar 

  117. Rauber, S. et al. Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells. Nat. Med 23, 938–944 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Carrega, P. et al. NCR + ILC3 concentrate in human lung cancer and associate with intratumoral lymphoid structures. Nat. Commun. 6, 8280 (2015).

    Article  CAS  PubMed  Google Scholar 

  119. Koh, J. et al. IL23-producing human lung cancer cells promote tumor growth via conversion of innate lymphoid cell 1 (ILC1) into ILC3. Clin. Cancer Res. 25, 4026–4037 (2019).

    Article  CAS  PubMed  Google Scholar 

  120. Irshad, S. et al. RORγt+ innate lymphoid cells promote lymph node metastasis of breast cancers. Cancer Res. 77, 1083–1096 (2017).

    Article  CAS  PubMed  Google Scholar 

  121. Fridman, W. H., Pagès, F., Saut̀s-Fridman, C., Galon, J. The immune contexture in human tumours: impact on clinical outcome. Nat. Rev. Cancer. 12, 298–306 (2012).

  122. Tsakiroglou, A. M. et al. Spatial proximity between T and PD-L1 expressing cells as a prognostic biomarker for oropharyngeal squamous cell carcinoma. Br. J. Cancer 122, 539–544 (2020).

    Article  CAS  PubMed  Google Scholar 

  123. Bouzin, C., Brouet, A., De Vriese, J., DeWever, J. & Feron, O. Effects of vascular endothelial growth factor on the lymphocyte-endothelium interactions: identification of caveolin-1 and nitric oxide as control points of endothelial cell anergy. J. Immunol. 178, 1505–1511 (2007).

    Article  CAS  PubMed  Google Scholar 

  124. Buckanovich, R. J. et al. Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat. Med. 14, 28–36 (2008).

    Article  CAS  PubMed  Google Scholar 

  125. Shrimali, R. K. et al. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. 70, 6171–6180 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Yu, J. S. et al. Intratumoral T cell subset ratios and Fas ligand expression on brain tumor endothelium. J. Neurooncol. 64, 55–61 (2003).

    PubMed  Google Scholar 

  127. Bajou, K. et al. Plasminogen activator inhibitor-1 protects endothelial cells from FasL-mediated apoptosis. Cancer Cell 14, 324–334 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Motz, G. T. et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat. Med. 20, 607–615 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Valkenburg, K. C., De Groot, A. E., Pienta, K. J. Targeting the tumour stroma to improve cancer therapy. Nat. Rev. Clin. Oncol. 15, 366–381 (2018).

  130. Bazzichetto, C. et al. Advances in tumor-stroma interactions: emerging role of cytokine network in colorectal and pancreatic cancer. J. Oncol. 2019. https://www.ncbi.nlm.nih.gov/pubmed/31191652 (2019).

  131. Di Caro, G. et al. Occurrence of tertiary lymphoid tissue is associated with T-cell infiltration and predicts better prognosis in early-stage colorectal cancers. Clin. Cancer Res. 20, 2147–2158 (2014).

    Article  PubMed  CAS  Google Scholar 

  132. Graham, D. M. & Appelman, H. D. Crohn’s-like lymphoid reaction and colorectal carcinoma: a potential histologic prognosticator. Mod. Pathol. 3, 332–335 (1990).

    CAS  PubMed  Google Scholar 

  133. Pagès, F., Galon, J. & Fridman, W. H. The essential role of the in situ immune reaction in human colorectal cancer. J. Leukoc. Biol. 84, 981–987 (2008).

    Article  PubMed  CAS  Google Scholar 

  134. Thaunat, O. et al. Chronic rejection triggers the development of an aggressive intragraft immune response through recapitulation of lymphoid organogenesis. J. Immunol. 185, 717–728 (2010).

    Article  CAS  PubMed  Google Scholar 

  135. Lee, R. S. et al. Indirect recognition of allopeptides promotes the development of cardiac allograft vasculopathy. Proc. Natl Acad. Sci. USA. 98, 3276–3281 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Neyt K., Perros F., GeurtsvanKessel C. H., Hammad H., Lambrecht B. N. Tertiary lymphoid organs in infection and autoimmunity. Trends Immunol. 33, 297–305. https://doi.org/10.1016/j.it.2012.04.006 (2012).

  137. Lee, Y. et al. Recruitment and activation of naive T cells in the islets by lymphotoxin β receptor-dependent tertiary lymphoid structure. Immunity 25, 499–509 (2006).

    Article  CAS  PubMed  Google Scholar 

  138. Cabrita, R. et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature 577, 561–565 (2020).

    Article  CAS  PubMed  Google Scholar 

  139. Meier, D. et al. Ectopic lymphoid-organ development occurs through interleukin 7-mediated enhanced survival of lymphoid-tissue-inducer cells. Immunity 26, 643–654 (2007).

    Article  CAS  PubMed  Google Scholar 

  140. Furtado, G. C. et al. Lymphotoxin β receptor signaling is required for inflammatory lymphangiogenesis in the thyroid. Proc. Natl. Acad. Sci. USA. 104, 5026–5031 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Peters, A. et al. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity 35, 986–996 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Deteix, C. et al. Intragraft Th17 infiltrate promotes lymphoid neogenesis and hastens clinical chronic rejection. J. Immunol. 184, 5344–5351 (2010).

    Article  CAS  PubMed  Google Scholar 

  143. Guedj, K. et al. M1 macrophages act as LTβR-independent lymphoid tissue inducer cells during atherosclerosis-related lymphoid neogenesis. Cardiovasc Res. 101, 434–443 (2014).

    Article  CAS  PubMed  Google Scholar 

  144. Lochner, M. et al. Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORγt and LTi cells. J. Exp. Med. 208, 125–134 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Vondenhoff, M. F. et al. LTβR signaling induces cytokine expression and up-regulates lymphangiogenic factors in lymph node anlagen. J. Immunol. 182, 5439–5445 (2009).

    Article  CAS  PubMed  Google Scholar 

  146. Martinet, L. et al. High endothelial venules (HEVs) in human melanoma lesions: major gateways for tumor-infiltrating lymphocytes. Oncoimmunology 1, 829–839 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Streeter, P. R., Rouse, B. T. & Butcher, E. C. Immunohistologic and functional characterization of a vascular addressin involved in lymphocyte homing into peripheral lymph nodes. J. Cell Biol. 107, 1853–1862 (1988).

    Article  CAS  PubMed  Google Scholar 

  148. Nurieva, R. I. et al. Bcl6 mediates the development of T follicular helper cells. Science 325, 1001–1005 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Schmitt, N. et al. The cytokine TGF-β 2 co-opts signaling via STAT3-STAT4 to promote the differentiation of human T FH cells. Nat. Immunol. 15, 856–865 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Locci, M. et al. Activin A programs the differentiation of human T FH cells. Nat. Immunol. 17, 976–984 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Nurieva, R. I. et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29, 138–149 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Karnowski, A. et al. B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1. J. Exp. Med. 209, 2049–2064 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Rasheed, A. U., Rahn, H. P., Sallusto, F., Lipp, M. & Müller, G. Follicular B helper T cell activity is confined to CXCR5hiICOShi CD4 T cells and is independent of CD57 expression. Eur. J. Immunol. 36, 1892–1903 (2006).

    Article  CAS  PubMed  Google Scholar 

  154. Heesters, B. A. et al. Endocytosis and recycling of immune complexes by follicular dendritic cells enhances B cell antigen binding and activation. Immunity 38, 1164–1175 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Garin, A. et al. Toll-like receptor 4 signaling by follicular dendritic cells is pivotal for germinal center onset and affinity maturation. Immunity 33, 84–95 (2010).

    Article  CAS  PubMed  Google Scholar 

  156. Cazac, B. B. & Roes, J. TGF-β receptor controls B cell responsiveness and induction of IgA in vivo. Immunity 13, 443–451 (2000).

    Article  CAS  PubMed  Google Scholar 

  157. Dieu-Nosjean, M. C., Goc, J., Giraldo, N. A., Sautès-Fridman, C. & Fridman, W. H. Tertiary lymphoid structures in cancer and beyond. Trends Immunol. 35, 571–580 (2014).

    Article  CAS  PubMed  Google Scholar 

  158. Posch, F. et al. Maturation of tertiary lymphoid structures and recurrence of stage II and III colorectal cancer. Oncoimmunology 7, e1378844 (2018).

    Article  PubMed  Google Scholar 

  159. Yamaguchi, K. et al. Helper T cell-dominant tertiary lymphoid structures are associated with disease relapse of advanced colorectal cancer. Oncoimmunology. 9, 1724763 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Silina, K. et al. Germinal centers determine the prognostic relevance of tertiary lymphoid structures and are impaired by corticosteroids in lung squamous cell carcinoma. Cancer Res. 78, 1308–1320 (2018).

    Article  CAS  PubMed  Google Scholar 

  161. Germain, C. et al. Presence of B cells in tertiary lymphoid structures is associated with a protective immunity in patients with lung cancer. Am. J. Respir. Crit. Care Med. 189, 832–844 (2014).

    Article  CAS  PubMed  Google Scholar 

  162. Bindea, G. et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39, 782–795 (2013).

    Article  CAS  PubMed  Google Scholar 

  163. Schürch, C. M. et al. Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front. bioRxiv. 743989 (2019).

  164. Ansel, K. M. et al. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406, 309–314 (2000).

    Article  CAS  PubMed  Google Scholar 

  165. Thommen, D. S. et al. A transcriptionally and functionally distinct pd-1 + cd8 + t cell pool with predictive potential in non-small-cell lung cancer treated with pd-1 blockade. Nat. Med. 24, 994–1004 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Workel, H. H. et al. A transcriptionally distinct CXCL13þCD103þCD8þ T-cell population is associated with b-cell recruitment and neoantigen load in human cancer. Cancer Immunol. Res. 7, 784–796 (2019).

    Article  CAS  PubMed  Google Scholar 

  167. Barnes, T. A., Amir, E. HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer. Br. J. Cancer. 117, 451–460 (2017).

  168. Hwang, C. et al. Stromal tumor-infiltrating lymphocytes evaluated on H&E-stained slides are an independent prognostic factor in epithelial ovarian cancer and ovarian serous carcinoma. Oncol. Lett. 17, 4557–4565 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. James, F. R. et al. Association between tumour infiltrating lymphocytes, histotype and clinical outcome in epithelial ovarian cancer. BMC Cancer 17, 657 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Salgado, R. et al. Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: a secondary analysis of the NeoALTTO trial. JAMA Oncol. 1, 448–455 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Luen, S. J. et al. Tumour-infiltrating lymphocytes in advanced HER2-positive breast cancer treated with pertuzumab or placebo in addition to trastuzumab and docetaxel: a retrospective analysis of the CLEOPATRA study. Lancet Oncol. 18, 52–62 (2017).

    Article  CAS  PubMed  Google Scholar 

  172. Denkert, C. et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J. Clin. Oncol. 33, 983–991 (2015).

    Article  CAS  PubMed  Google Scholar 

  173. Rim, S. Kim. & Stromal. et al. Tumor-infiltrating lymphocytes in NRG oncology/NSABP B-31 adjuvant trial for early-stage HER2-positive breast cancer. J. Natl Cancer Inst. 111, 867–871 (2019).

    Article  CAS  Google Scholar 

  174. Fuchs, T. L. et al. Assessment of tumor-infiltrating lymphocytes using international TILs working group (ITWG) system is a strong predictor of overall survival in colorectal carcinoma. Am. J. Surg. Pathol. 44, 536–544 (2020).

    Article  PubMed  Google Scholar 

  175. Hendry, S. et al. Assessing tumor-infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the international immunooncology biomarkers working group: Part 1: assessing the host immune response, TILs in invasive breast carcinoma and ductal carcinoma in situ, metastatic tumor deposits and areas for further research. Adv Anatomic Pathol. 24, 235–251 (2017).

  176. Hendry, S. et al. Assessing tumor-infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the international immuno-oncology biomarkers working group: Part 2: TILs in melanoma, gastrointestinal tract carcinom. Adv. Anatomic Pathol. 24, 311–335 (2017).

  177. The Royal College of Pathologists of Australasia. Colorectal Cancer, Structured Reporting Protocol. (3rd ed). 1–77. (The Royal College of Pathologists of Australasia, 2016).

  178. Cui, Y., Zhang, G., Liu, Z., Xiong, Z. & Hu, J. A deep learning algorithm for one-step contour aware nuclei segmentation of histopathology images. Med Biol. Eng. Comput. 57, 2027–2043 (2019).

    Article  PubMed  Google Scholar 

  179. Pagès, F. et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet 391, 2128–2139 (2018).

    Article  PubMed  Google Scholar 

  180. Mlecnik, B. et al. Comprehensive intrametastatic immune quantification and major impact of immunoscore on survival. J. Natl Cancer Inst. 110, 97–108 (2018).

    Article  CAS  Google Scholar 

  181. Zhou, C. et al. Development and validation of a seven-immune-feature-based prognostic score for oral squamous cell carcinoma after curative resection. Int. J. Cancer 146, 1152–1163 (2020).

    Article  CAS  PubMed  Google Scholar 

  182. Shaban, M. et al. A novel digital score for abundance of tumour infiltrating lymphocytes predicts disease free survival in oral squamous cell carcinoma. Sci. Rep. 9, 1–13 (2019).

    Article  CAS  Google Scholar 

  183. Zeng, D. et al. Gene expression profiles for a prognostic immunoscore in gastric cancer. Br. J. Surg. 105, 1338–1348 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Li, X. D. et al. Prognostic role of the immunoscore for patients with urothelial carcinoma of the bladder who underwent radical cystectomy. Ann. Surg. Oncol. 26, 4148–4156 (2019).

    Article  PubMed  Google Scholar 

  185. Bychkov, D. et al. Deep learning based tissue analysis predicts outcome in colorectal cancer. Sci. Rep. 8, 1–11 (2018).

    Article  CAS  Google Scholar 

  186. Ronneberger, O., Fischer, P., Brox, T. U-Net: Convolutional Networks for Biomedical Image Segmentation. http://lmb.informatik.uni-freiburg.de/.

  187. Kurc, T. et al. Segmentation and classification in digital pathology for glioma research: challenges and deep learning approaches. Front Neurosci. 14, 27 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  188. Coudray, N., Santiago Ocampo, P. Classification and mutation prediction from non–small cell lung cancer histopathology images using deep learning. Nat Med. https://doi.org/10.1038/s41591-018-0177-5.

  189. Bejnordi, B. E. et al. Diagnostic assessment of deep learning algorithms for detection of lymph node metastases in women with breast cancer. JAMA. 318, 2199–2210 (2017).

    Article  Google Scholar 

  190. Jiang, Y. et al. ImmunoScore Signature. Ann. Surg. 267, 504–513 (2018).

    Article  PubMed  Google Scholar 

  191. Tahkola, K. et al. High immune cell score predicts improved survival in pancreatic cancer. Virchows Arch. 472, 653–665 (2018).

    Article  CAS  PubMed  Google Scholar 

  192. Gide, T. N. et al. Distinct immune cell populations define response to anti-PD-1 monotherapy and anti-PD-1/anti-CTLA-4 combined therapy. Cancer Cell 35, 238–255.e6 (2019).

    Article  CAS  PubMed  Google Scholar 

  193. Wu, T. D. et al. Peripheral T cell expansion predicts tumour infiltration and clinical response. Nature 579, 274–278 (2020).

    Article  CAS  PubMed  Google Scholar 

  194. Araujo, B. et al. Common phenotypic dynamics of tumor-infiltrating lymphocytes across different histologies upon checkpoint inhibition: impact on clinical outcome. Cytotherapy 22, 204–213 (2020).

    Article  CAS  Google Scholar 

  195. Thommen, D. S. et al. A transcriptionally and functionally distinct pd-1 + cd8 + t cell pool with predictive potential in non-small-cell lung cancer treated with pd-1 blockade. Nat. Med. 24, 994–1004 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Arce Vargas, F. et al. Fc effector function contributes to the activity of human anti-CTLA-4 antibodies. Cancer Cell 33, 649–663.e4 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Kamada, T. et al. PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc. Natl Acad. Sci. USA 116, 9999–10008 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Yost, K. E. et al. Clonal replacement of tumor-specific T cells following PD-1 blockade. Nat. Med. 25, 1251–1259 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Hogan, S. A. et al. Peripheral blood TCR repertoire profiling may facilitate patient stratification for immunotherapy against melanoma. http://www.imgt.org (2019).

  200. Rizvi, N. A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 351, 1463–1469 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Eggink, F. A. et al. Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition. Oncoimmunology 6, e1264565 (2017).

    Article  PubMed  CAS  Google Scholar 

  203. Yamashita, H. et al. Microsatellite instability is a biomarker for immune checkpoint inhibitors in endometrial cancer. Oncotarget 9, 5652–5664 (2018).

    Article  PubMed  Google Scholar 

  204. Jones, N. L., Xiu, J., Rocconi, R. P., Herzog, T. J. & Winer, I. S. Immune checkpoint expression, microsatellite instability, and mutational burden: Identifying immune biomarker phenotypes in uterine cancer. Gynecol. Oncol. 156, 393–399 (2020).

    Article  CAS  PubMed  Google Scholar 

  205. Maby, P. et al. Correlation between density of CD8+ T-cell infiltrate in microsatellite unstable colorectal cancers and frameshift mutations: A rationale for personalized immunotherapy. Cancer Res. 75, 3446–3455 (2015).

    Article  CAS  PubMed  Google Scholar 

  206. Gryfe, R. et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N. Engl. J. Med 342, 69–77 (2000).

    Article  CAS  PubMed  Google Scholar 

  207. Petrelli F., Ghidini M., Ghidini A., Tomasello G. Outcomes following immune checkpoint inhibitor treatment of patients with microsatellite instability-high cancers. JAMA Oncol. https://jamanetwork.com/journals/jamaoncology/fullarticle/2765752 (2020).

  208. Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 357, 409–413 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Forde, P. M. et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N. Engl. J. Med. 378, 1976–1986 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Blank, C. U. et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat. Med. 24, 1655–1661 (2018).

    Article  CAS  PubMed  Google Scholar 

  211. Chalabi, M. et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat. Med. 26, 566–576 (2020).

    Article  CAS  PubMed  Google Scholar 

  212. Hellmann, M. D. et al. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell 33, 843–852.e4 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Boland, J. L. et al. Early disease progression and treatment discontinuation in patients with advanced ovarian cancer receiving immune checkpoint blockade. Gynecol. Oncol. 152, 251–258 (2019).

    Article  PubMed  Google Scholar 

  214. Adams, S. et al. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study. Ann. Oncol. 30, 397–404 (2019).

    Article  CAS  PubMed  Google Scholar 

  215. Beer, T. M. et al. Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer. J. Clin. Oncol. 35, 40–47 (2017).

    Article  CAS  PubMed  Google Scholar 

  216. Subudhi, S. K. et al. Neoantigen responses, immune correlates, and favorable outcomes after ipilimumab treatment of patients with prostate cancer. Sci. Transl. Med. 12, eaaz3577 (2020).

    Article  CAS  PubMed  Google Scholar 

  217. Adams, S. et al. Atezolizumab plus nab-paclitaxel in the treatment of metastatic triple-negative breast cancer with 2-year survival follow-up. JAMA Oncol. 5, 334 (2019).

    Article  PubMed  Google Scholar 

  218. Voorwerk, L. et al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nat. Med. 25, 920–928 (2019).

    Article  CAS  PubMed  Google Scholar 

  219. Keskin, D. B. et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 565, 234–239 (2019).

    Article  CAS  PubMed  Google Scholar 

  220. Zhang, Q. et al. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat. Immunol. 19, 723–732 (2018).

    Article  CAS  PubMed  Google Scholar 

  221. Van Hall, T. et al. Monalizumab: inhibiting the novel immune checkpoint NKG2A. J. ImmunoTher. Cancer. 7, 263 (2019).

  222. Tinker, A. V. et al. Dose-ranging and cohort-expansion study of monalizumab (IPH2201) in patients with advanced gynecologic malignancies: a trial of the canadian cancer trials group (CCTG): IND221. Clin. Cancer Res. 25, 6052–6060 (2019).

    Article  CAS  PubMed  Google Scholar 

  223. André, P. et al. Anti-NKG2A mAb Is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell 175, 1731–1743.e13 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  224. Rohaan, M. W., Wilgenhof, S., Haanen, J. B. A. G. Adoptive cellular therapies: the current landscape. Virchows Archiv. 474, 449–461 /pmc/articles/PMC6447513/?report=abstract (2019).

  225. Garrido, F., Ruiz-Cabello, F., Aptsiauri, N. Rejection versus escape: the tumor MHC dilemma. Cancer Immunol. Immunother. 66, 259–271. https://pubmed.ncbi.nlm.nih.gov/28040849/ (2017).

  226. Guedan, S., Calderon, H., Posey, A. D., Maus, M. V. Engineering and design of chimeric antigen receptors. Mol. Ther. 12, 145–156. https://doi.org/10.1016/j.omtm.2018.12.009 (2019).

  227. Met, Ö., Jensen, K. M., Chamberlain, C. A., Donia, M., Svane, I. M. Principles of adoptive T cell therapy in cancer. Semin Immunopathol. 41, 49–58. https://doi.org/10.1007/s00281-018-0703-z (2019).

  228. Chandran, S. S. & Klebanoff, C. A. T cell receptor‐based cancer immunotherapy: emerging efficacy and pathways of resistance. Immunol. Rev. 290, 127–147 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Tran, E. et al. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science 350, 1387–1390 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Tran, E. et al. T-cell transfer therapy targeting mutant KRAS in cancer. N. Engl. J. Med. 3752, 255–262 (2016).

    Google Scholar 

  231. Zacharakis, N. et al. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat. Med. 24, 724–730 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Radvanyi, L. G. et al. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Clin. Cancer Res. 18, 6758–6770 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Joalland, N., Scotet, E. Emerging challenges of preclinical models of anti-tumor immunotherapeutic strategies utilizing Vγ9Vδ2 T Cells. Front Immunol. 11, 992 https://pubmed.ncbi.nlm.nih.gov/32528477/ (2020).

  234. Mao, T. L. et al. Ex vivo expanded human Vγ9vδ2 T-cells can suppress epithelial ovarian cancer cell growth. Int J Mol Sci. 20, 1139 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  235. Dieli, F. et al. Targeting human γδ T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer. Cancer Res. 67, 7450–7457 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Meraviglia, S. et al. In vivo manipulation of V9V2 T cells with zoledronate and low-dose interleukin-2 for immunotherapy of advanced breast cancer patients. Clin. Exp. Immunol. 161, 290–297 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. June, C. H., O’Connor, R. S., Kawalekar, O. U., Ghassemi, S., Milone, M. C. CAR T cell immunotherapy for human cancer. Science. 359, 1361–1365. http://science.sciencemag.org/ (2018).

  238. Lu, Y. et al. Complement signals determine opposite effects of B cells in chemotherapy-induced immunity. Cell 180, 1081–1097.e24 (2020).

    Article  CAS  PubMed  Google Scholar 

  239. Griss, J. et al. B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma. Nat. Commun. 10, 1–14 (2019).

    Article  CAS  Google Scholar 

  240. Cabrita, R. et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature 577, 561 (2020).

    Article  CAS  PubMed  Google Scholar 

  241. Petitprez, F. et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature 577, 556–60. (2020).

    Article  CAS  PubMed  Google Scholar 

  242. Liu, Z. & Fu, Y. X. Chemotherapy induces cancer-fighting B cells. Cell 180, 1037–1039 (2020).

    Article  CAS  PubMed  Google Scholar 

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  1. These authors contributed equally: Sterre T. Paijens, Annegé Vledder

  2. These authors jointly supervised this work: Marco de Bruyn, Hans W. Nijman

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  1. Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Sterre T. Paijens, Annegé Vledder, Marco de Bruyn & Hans W. Nijman

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A.V. and S.T.P. contributed equally to the design and writing of the manuscript. M.B. and H.W.N. designed and supervised the writing of the manuscript.

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Paijens, S.T., Vledder, A., de Bruyn, M. et al. Tumor-infiltrating lymphocytes in the immunotherapy era. Cell Mol Immunol 18, 842–859 (2021). https://doi.org/10.1038/s41423-020-00565-9

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