Current Topics In Breast pathologyTumour-infiltrating lymphocytes and the emerging role of immunotherapy in breast cancer
Introduction
Ample evidence confirms host anti-tumour immunity can play a key deterministic role in the outcome of cancerous cells. Evasion of immune influences is considered a hallmark of cancer.1 An encompassing hypothesis is the immunoediting theory, whereby host immunosurveillance recognises immunogenic tumour antigens and responds in three subsequent phases: elimination, equilibrium, and escape.2, 3 Left unchecked, these processes shape the clonal and genomic structure of tumours towards a state where the tumour can escape immune containment, the most frequent point of diagnosis. More recently, it has become evident that immunoediting alone is insufficient to fully explain the lack or loss of immunogenicity of a tumour. Indeed, as we increasingly explore personalised medicine, we are beginning to unravel genomic alterations that may provide tumour-intrinsic mechanisms of immune escape, demonstrating an intriguing interaction between host and tumour factors.4, 5, 6
Tumour-infiltrating lymphocytes (TILs), observed as mononuclear immune cells nested in and around neoplastic cells, stand at the very heart of this interaction. Numerous retrospective analyses of tumour samples from prospective trials have confirmed TILs to be a robust and reproducible biomarker of immunogenicity in selected breast cancer subtypes. While providing valuable insights, a more complete understanding of the biological significance of TILs is hampered by heterogeneity of TIL evaluation and trial design. Regardless, as we enter a new era of immunotherapeutics, TILs will become increasingly relevant as a biomarker in our efforts to tailor therapies to maximum effect. This review aims to discuss the evaluation of TILs, its clinical relevance, and its potential role in the future treatment of breast cancer with immunotherapies.
Section snippets
Evaluating TILs
TILs encompass a mixture of different cell types usually dominated by T cells, with variable proportions of B cells, NK cells, macrophages, and dendritic cells.7, 8 TIL quantification and characterisation therefore have been used as a surrogate for evaluation of tumour immunogenicity. Of note, a chronically sustained immune response is generally considered to be counter-productive in human disease and so mechanisms of immunosupression inevitably establish.9 Indeed, chronic inflammation can
Methods of TIL evaluation
TILs have been evaluated by various methodologies described below. Studies evaluating TILs have rapidly expanded in recent years, largely by virtue of retrospective analysis of prospectively collected tumour samples in early breast cancer clinical trials. These have served as ideal platforms to investigate the prognostic and predictive influences of host anti-tumour immunity.
The immunogenicity of breast cancer
TILs have been observed across many cancers; however, the considerable diversity in quantity and types of infiltrates implies that some tumour types are more immunogenic than others.37, 38 Although lymphocytic infiltrates have long been observed in breast cancer,39 it has not previously been considered particularly immunogenic, unlike melanoma and renal cell carcinoma.
The clinical relevance of TILs in breast cancer
The influences of host anti-tumour immunity on breast cancer disease biology have been best demonstrated in retrospective analyses of prospectively collected tumour tissue from clinical trials and well described patient cohorts. The prognostic and predictive associations are summarised (Table 3, Table 4). It should be noted that all of the summarised analyses are from evaluation of primary breast cancers in the setting of early breast cancer. The relevance of TILs in metastatic tissue and in
Therapeutic immunomodulation
Several studies have demonstrated that response to conventional anticancer agents (chemotherapy, radiotherapy, targeted therapy) may be partly mediated by effects on immunity, either via stimulation of immunogenicity or by modulation of the immune microenvironment within a tumour.65, 66 Therefore, there is substantial interest in the potential of stimulating immunogenicity by conversion of a low TIL tumour to a high TIL tumour. Increases in TIL levels and changes to the tumour immune milieu
The future of TILs in the context of immunotherapies
Immune checkpoint therapies are at the forefront of a range of immunotherapies currently being utilised in breast cancer in clinical trial settings, as well as in the community. To understand the interaction between pre-existing host immune responses and the efficacy of checkpoint blockade, it is crucial to accurately and reliably document tumour immune infiltrates. Simple quantitative TIL evaluation of H&E sections represents a validated, reproducible, and inexpensive methodology. Furthermore,
Conclusion
Widespread evaluation of TILs across all breast cancer subtypes has uncovered important revelations about the interaction between tumour and host immune responses. Heterogeneous methodologies have been employed, however findings are largely consistent. While breast cancer has not previously been considered particularly immunogenic, multiple studies suggest an important influence of host anti-tumour immunity on response to therapy and prognosis, most notably in HER2 positive and triple negative
Acknowledgements
SL is supported by the John Colebatch Fellowship, Cancer Council Victoria, and the Breast Cancer Research Foundation (BCRF), New York.
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