Abstract
The presence of tumour-infiltrating lymphocytes (TILs) is associated with favourable outcomes in patients with breast cancer as well as in those with other solid tumours. T cells make up a considerable proportion of TILs and current evidence suggests that CD8+ T cells are a crucial determinant of favourable clinical outcomes. Studies involving tumour material from numerous solid tumour types, including breast cancer, demonstrate that the CD8+ TILs include a subpopulation of tissue-resident memory T (TRM) cells. This subpopulation has features consistent with those of TRM cells, which have been described as having a role in peripheral immune surveillance and viral immunity in both humans and mice. Patients with early-stage triple-negative breast cancers harbouring greater numbers of TRM cells have a substantially improved prognosis and longer overall survival. Furthermore, patients with advanced-stage breast cancers with higher levels of TRM cells have increased response rates to anti-PD-1 antibodies. These findings have motivated efforts to explore whether CD8+ TRM cells include tumour-specific T cells, their functional responses to cognate antigens and their role in responses to immune checkpoint inhibition. In this Review, we focus on the clinical significance of CD8+ TRM cells and the potential ways that these cells can be targeted to improve the success of immunotherapeutic approaches in patients with breast cancer, as well as in those with other solid tumour types.
Key points
-
The clinical and biological importance of qualitative differences in tumour-infiltrating lymphocyte (TIL) populations in patients with solid tumours, including breast cancer, is an area of intensive research.
-
Quantification of TILs is a reliable and robust prognostic biomarker in the management of patients with breast cancer, particularly in those with the triple-negative or HER2-overexpressing disease subtypes.
-
CD8+ tissue-resident memory T (TRM) cells have been identified as TILs in patients with various solid tumours, including those with breast cancer, and are a distinct subpopulation of CD8+ TILs.
-
High levels of expression of a TRM cell signature derived from single-cell RNA sequencing are associated with a favourable prognosis and an increased likelihood of a response to the anti-PD-1 antibody pembrolizumab in patients with triple-negative breast cancers, thus supporting the importance of this immune subset.
-
TRM cells express high levels of cytotoxic molecules, such as granzymes, and immune-checkpoint proteins and might be a key TIL subset targeted by several immunotherapies.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Savas, P. et al. Clinical relevance of host immunity in breast cancer: from TILs to the clinic. Nat. Rev. Clin. Oncol. 13, 228–241 (2016).
Salgado, R. et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann. Oncol. 26, 259–271 (2015).
Loi, S. et al. Tumor-infiltrating lymphocytes and prognosis: a pooled individual patient analysis of early-stage triple-negative breast cancers. J. Clin. Oncol. 37, 559–569 (2019).
Loi, S. et al. Relationship between tumor infiltrating lymphocyte (TIL) levels and response to pembrolizumab (pembro) in metastatic triple-negative breast cancer (mTNBC): results from KEYNOTE-086 [abstract LBA13]. Ann. Oncol. 28 (Suppl. 5), mdx440.005 (2017).
Loi, S. et al. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial. Lancet Oncol. 20, 371–382 (2019).
Wein, L., Luen, S. J., Savas, P., Salgado, R. & Loi, S. Checkpoint blockade in the treatment of breast cancer: current status and future directions. Br. J. Cancer 119, 4–11 (2018).
Cardoso, F. et al. Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 30, 1194–1220 (2019).
Ali, H. R. et al. Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann. Oncol. 25, 1536–1543 (2014).
Savas, P. et al. Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat. Med. 24, 986–993 (2018).
Masopust, D. & Soerens, A. G. Tissue-resident T cells and other resident leukocytes. Annu. Rev. Immunol. 37, 521–546 (2019).
Yau, C. et al. Expression-based immune signatures as predictors of neoadjuvant targeted-/chemo-therapy response: Experience from the I-SPY 2 TRIAL of ~1000 patients across 10 therapies [abstract]. Cancer Res. 79 (Suppl. 4), P3-10-06 (2019).
Adams, S. et al. Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study. Ann. Oncol. 30, 405–411 (2019).
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).
Loi, S. et al. RNA molecular signatures as predictive biomarkers of response to monotherapy pembrolizumab in patients with metastatic triple-negative breast cancer: KEYNOTE-086 [abstract]. Cancer Res. 79 (Suppl. 13), LB-225 (2019).
Wang, Z. Q. et al. CD103 and intratumoral immune response in breast cancer. Clin. Cancer Res. 22, 6290–6297 (2016).
Edwards, J. et al. CD103+ tumor-resident CD8+ T cells are associated with improved survival in immunotherapy-naive melanoma patients and expand significantly during anti-PD-1 treatment. Clin. Cancer Res. 24, 3036–3045 (2018).
Murray, T. et al. Very late antigen-1 marks functional tumor-resident CD8 T cells and correlates with survival of melanoma patients. Front. Immunol. 7, 573 (2016).
Boddupalli, C. S. et al. Interlesional diversity of T cell receptors in melanoma with immune checkpoints enriched in tissue-resident memory T cells. JCI Insight 1, e88955 (2016).
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).
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).
Koh, J. et al. Prognostic implications of intratumoral CD103+ tumor-infiltrating lymphocytes in pulmonary squamous cell carcinoma. Oncotarget 8, 13762–13769 (2017).
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).
Komdeur, F. L. et al. CD103+ intraepithelial T cells in high-grade serous ovarian cancer are phenotypically diverse TCRαβ+ CD8αβ+ T cells that can be targeted for cancer immunotherapy. Oncotarget 7, 75130–75144 (2016).
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).
Webb, J. R., Milne, K., Watson, P., Deleeuw, R. J. & Nelson, B. H. Tumor-infiltrating lymphocytes expressing the tissue resident memory marker CD103 are associated with increased survival in high-grade serous ovarian cancer. Clin. Cancer Res. 20, 434–444 (2014).
Duhen, T. et al. Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nat. Commun. 9, 2724 (2018).
Komdeur, F. L. et al. CD103+ tumor-infiltrating lymphocytes are tumor-reactive intraepithelial CD8+ T cells associated with prognostic benefit and therapy response in cervical cancer. Oncoimmunology 6, e1338230 (2017).
Workel, H. H. et al. CD103 defines intraepithelial CD8+ PD1+ tumour-infiltrating lymphocytes of prognostic significance in endometrial adenocarcinoma. Eur. J. Cancer 60, 1–11 (2016).
Ling, K. L. et al. Modulation of CD103 expression on human colon carcinoma-specific CTL. J. Immunol. 178, 2908–2915 (2007).
Wang, B. et al. CD103+ tumor infiltrating lymphocytes predict a favorable prognosis in urothelial cell carcinoma of the bladder. J. Urol. 194, 556–562 (2015).
Lohneis, P. et al. Cytotoxic tumour-infiltrating T lymphocytes influence outcome in resected pancreatic ductal adenocarcinoma. Eur. J. Cancer 83, 290–301 (2017).
Gebhardt, T. et al. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat. Immunol. 10, 524–530 (2009).
Masopust, D. et al. Dynamic T cell migration program provides resident memory within intestinal epithelium. J. Exp. Med. 207, 553–564 (2010).
Cyster, J. G. & Schwab, S. R. Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu. Rev. Immunol. 30, 69–94 (2012).
Schon, M. P. et al. Mucosal T lymphocyte numbers are selectively reduced in integrin alpha E (CD103)-deficient mice. J. Immunol. 162, 6641–6649 (1999).
Gorfu, G., Rivera-Nieves, J. & Ley, K. Role of β7 integrins in intestinal lymphocyte homing and retention. Curr. Mol. Med. 9, 836–850 (2009).
Allakhverdi, Z. et al. Expression of CD103 identifies human regulatory T-cell subsets. J. Allergy Clin. Immunol. 118, 1342–1349 (2006).
Shiow, L. R. et al. CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature 440, 540–544 (2006).
Steinert, E. M. et al. Quantifying memory CD8 T cells reveals regionalization of immunosurveillance. Cell 161, 737–749 (2015).
Fernandez-Ruiz, D. et al. Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection. Immunity 45, 889–902 (2016).
Park, S. L., Gebhardt, T. & Mackay, L. K. Tissue-resident memory T cells in cancer immunosurveillance. Trends Immunol. 40, 735–747 (2019).
Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486–499 (2015).
Blank, C. U. et al. Defining ‘T cell exhaustion’. Nat. Rev. Immunol. 19, 665–674 (2019).
Kallies, A., Zehn, D. & Utzschneider, D. T. Precursor exhausted T cells: key to successful immunotherapy? Nat. Rev. Immunol. 20, 128–136 (2020).
Beura, L. K. et al. Intravital mucosal imaging of CD8(+) resident memory T cells shows tissue-autonomous recall responses that amplify secondary memory. Nat. Immunol. 19, 173–182 (2018).
Park, S. L. et al. Local proliferation maintains a stable pool of tissue-resident memory T cells after antiviral recall responses. Nat. Immunol. 19, 183–191 (2018).
Clarke, J. et al. Single-cell transcriptomic analysis of tissue-resident memory T cells in human lung cancer. J. Exp. Med. 216, 2128–2149 (2019).
Simoni, Y. et al. Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 557, 575–579 (2018).
Herndler-Brandstetter, D. et al. KLRG1+ effector CD8+ T cells lose KLRG1, differentiate into all memory T cell lineages, and convey enhanced protective immunity. Immunity 48, 716–729 (2018).
Schenkel, J. M. et al. IL-15-independent maintenance of tissue-resident and boosted effector memory CD8 T cells. J. Immunol. 196, 3920–3926 (2016).
Boutet, M. et al. TGFβ signaling intersects with CD103 integrin signaling to promote T-lymphocyte accumulation and antitumor activity in the lung tumor microenvironment. Cancer Res. 76, 1757–1769 (2016).
Mackay, L. K. et al. T-box transcription factors combine with the cytokines TGF-β and IL-15 to control tissue-resident memory T cell fate. Immunity 43, 1101–1111 (2015).
El-Asady, R. et al. TGF-β-dependent CD103 expression by CD8(+) T cells promotes selective destruction of the host intestinal epithelium during graft-versus-host disease. J. Exp. Med. 201, 1647–1657 (2005).
Mami-Chouaib, F. et al. Resident memory T cells, critical components in tumor immunology. J. Immunother. Cancer 6, 87 (2018).
Goldberg, J. E. & Schwertfeger, K. L. Proinflammatory cytokines in breast cancer: mechanisms of action and potential targets for therapeutics. Curr. Drug Targets 11, 1133–1146 (2010).
Leek, R. D. et al. Association of tumour necrosis factor alpha and its receptors with thymidine phosphorylase expression in invasive breast carcinoma. Br. J. Cancer 77, 2246–2251 (1998).
Le Bourgeois, T. et al. Targeting T cell metabolism for improvement of cancer immunotherapy. Front. Oncol. 8, 237 (2018).
Zhang, Y. et al. Enhancing CD8(+) T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell 32, 377–391.e9 (2017).
Xu, Y. et al. Glycolysis determines dichotomous regulation of T cell subsets in hypoxia. J. Clin. Invest. 126, 2678–2688 (2016).
Pan, Y. et al. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 543, 252–256 (2017).
Pan, Y. & Kupper, T. S. Metabolic reprogramming and longevity of tissue-resident memory T cells. Front. Immunol. 9, 1347 (2018).
Menares, E. et al. Tissue-resident memory CD8+ T cells amplify anti-tumor immunity by triggering antigen spreading through dendritic cells. Nat. Commun. 10, 4401 (2019).
Park, S. L. et al. Tissue-resident memory CD8+ T cells promote melanoma–immune equilibrium in skin. Nature 565, 366–371 (2019).
Park, J. H. et al. Prognostic value of tumor-infiltrating lymphocytes in patients with early-stage triple-negative breast cancers (TNBC) who did not receive adjuvant chemotherapy. Ann. Oncol. 30, 1941–1949 (2019).
Auslander, N. et al. Robust prediction of response to immune checkpoint blockade therapy in metastatic melanoma. Nat. Med. 24, 1545–1549 (2018).
Schmid, P. et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N. Engl. J. Med. 379, 2108–2121 (2018).
Schmid, P. et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 21, 44–59 (2020).
Sade-Feldman, M. et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 175, 998–1013.e20 (2018).
Borsellino, G. et al. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110, 1225–1232 (2007).
Tang, L. et al. Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery. Nat. Biotechnol. 36, 707–716 (2018).
Smith, T. T. et al. In situ programming of leukaemia-specific T cells using synthetic DNA nanocarriers. Nat. Nanotechnol. 12, 813–820 (2017).
Hartana, C. A. et al. Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer. Clin. Exp. Immunol. 194, 39–53 (2018).
Salerno, E. P., Olson, W. C., McSkimming, C., Shea, S. & Slingluff, C. L. Jr. T cells in the human metastatic melanoma microenvironment express site-specific homing receptors and retention integrins. Int. J. Cancer 134, 563–574 (2014).
Webb, J. R. et al. Profound elevation of CD8+ T cells expressing the intraepithelial lymphocyte marker CD103 (αE/β7 integrin) in high-grade serous ovarian cancer. Gynecol. Oncol. 118, 228–236 (2010).
Quinn, E., Hawkins, N., Yip, Y. L., Suter, C. & Ward, R. CD103+ intraepithelial lymphocytes–a unique population in microsatellite unstable sporadic colorectal cancer. Eur. J. Cancer 39, 469–475 (2003).
Zhang, L. et al. Lineage tracking reveals dynamic relationships of T cells in colorectal cancer. Nature 564, 268–272 (2018).
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).
Li, B. et al. The landscape of antigen-specific T cells in human cancers. bioRxiv https://doi.org/10.1101/459842 (2018).
Acknowledgements
The work of S.L. is supported by the National Breast Cancer Foundation of Australia and the Breast Cancer Research Foundation (New York, NY, USA). The work of P.A.B. is supported by a National Breast Cancer Foundation of Australia Fellowship (ECF-17-005).
Author information
Authors and Affiliations
Contributions
A.B., P.S., S.S., R.L. and B.V. researched data for the article. A.B., L.K.M., P.J.N. and S.L. made a substantial contribution to discussions of the content. A.B., P.S., S.S., R.L., B.V. and S.L. wrote the manuscript. A.B., S.J.L., P.A.B., L.K.M., P.J.N. and S.L. reviewed and/or edited the manuscript prior to submission.
Corresponding author
Ethics declarations
Competing interests
S.L.’s institution receives research funding from Bristol-Myers Squibb, Eli Lilly, Genentech, Merck, Novartis, Pfizer, Puma Biotechnology and Roche. S.L. has acted as a non-compensated consultant of AstraZeneca, Bristol-Meyers Squibb, Merck, Novartis, Pfizer, Roche-Genentech and Seattle Genetics. P.J.N. receives research funding from Advaxis, Allergan, Bristol-Myers Squibb, Compugen, Juno-Celgene and Roche-Genentech. The other authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
RELATED LINKS
WHO classification of tumours online: https://tumourclassification.iarc.who.int/welcome/
Glossary
- Haemotoxylin and eosin (H&E) staining
-
A commonly used histopathological staining technique that enables the visualization of the cellular features of a clinical specimen.
- Biomarker
-
A naturally occurring feature of a tumour that can be measured and has prognostic and/or predictive value.
- Single-cell RNA sequencing
-
High-resolution sequencing of the RNA transcripts of individual cells using optimized next-generation sequencing technologies that confer a better understanding of cellular function.
- Gene signature
-
A group of genes expressed by a cell with a defined, unique and characteristic pattern of expression that reflects a specific genotype and/or phenotype.
- Multiplex immunohistochemistry
-
Labelling of protein structures on histological slides using antibodies conjugated to different fluorescent reporters that are able to render the multiple features visible.
- Flow cytometry
-
Analysis of single cells using a variety of cell-surface and intracellular fluorescent markers.
- CyTOF
-
High-throughput analysis of single cells using heavy metal tags followed by mass spectrometry.
- Cytokines
-
Small proteins secreted by immune cells that result in the paracrine stimulation of other cells.
- Chemokines
-
A family of cytokines that act as chemoattractants and promote the migration of responsive cells towards the site of an immune response.
- Immune checkpoint proteins
-
Protein markers expressed on the surface of immune cells that regulate their effector function and proliferation.
- Adoptive cell therapy
-
Transfer of immune cells, usually the patient’s own T cells following ex vivo modification and/or expansion, into a patient for therapeutic purposes.
Rights and permissions
About this article
Cite this article
Byrne, A., Savas, P., Sant, S. et al. Tissue-resident memory T cells in breast cancer control and immunotherapy responses. Nat Rev Clin Oncol 17, 341–348 (2020). https://doi.org/10.1038/s41571-020-0333-y
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41571-020-0333-y
This article is cited by
-
Identification of breast cancer subgroups and immune characterization based on glutamine metabolism-related genes
BMC Medical Genomics (2024)
-
Silencing PinX1 enhances radiosensitivity and antitumor-immunity of radiotherapy in non-small cell lung cancer
Journal of Translational Medicine (2024)
-
Multifunctional RGD coated a single-atom iron nanozyme: A highly selective approach to inducing ferroptosis and enhancing immunotherapy for pancreatic cancer
Nano Research (2024)
-
PIK3CA mutation-driven immune signature as a prognostic marker for evaluating the tumor immune microenvironment and therapeutic response in breast cancer
Journal of Cancer Research and Clinical Oncology (2024)
-
Prognostic values of tissue-resident CD8+T cells in human hepatocellular carcinoma and intrahepatic cholangiocarcinoma
World Journal of Surgical Oncology (2023)