Elsevier

Pathology

Volume 49, Issue 2, February 2017, Pages 141-155
Pathology

Current Topics In Breast pathology
Tumour-infiltrating lymphocytes and the emerging role of immunotherapy in breast cancer

https://doi.org/10.1016/j.pathol.2016.10.010Get rights and content

Summary

Breast cancer has not previously been considered a highly immunogenic cancer. Observations of tumour-infiltrating lymphocytes (TILs) in and around neoplastic cells in tumour samples, and associations with improved pathological complete response and clinical survival end points have changed our perspective on this. Lymphocytic infiltrates have long been observed in breast cancer; however, more recently, retrospective analysis of prospectively collected tissue samples from clinical trials has demonstrated the potential role of host immunosurveillance in influencing the biology of breast cancer. This association appears to be strongest in triple negative and HER2 positive breast cancer subtypes. Contrastingly, the association in luminal tumours is less clear, and is potentially limited by substantial tumoural heterogeneity. Several methodologies have been employed to quantify, and describe the composition of TILs, each with its own advantages and disadvantages. The results of these analyses have been generally consistent, and valuable efforts are currently underway to standardise the evaluation of TILs toward a universal approach. More technical methods of TIL characterisation remain important in the research setting. The evaluation of TILs becomes increasingly relevant with the emerging role of immunotherapy in breast cancer. Early phase trials of checkpoint blockade show promising results; however, it is likely that some patients will require combination treatments to maximise therapeutic benefits. Equally, some patients may not derive any benefit from immunotherapies. This underscores the importance of the development of relevant predictive biomarkers. As a key representative of the immune interaction between host and tumour, lymphocytic infiltrates are ideally placed for continued research into the determinants of immunogenicity, and response to immunotherapeutic approaches. In this review, we will discuss the current methodologies of evaluation, and the clinical relevance of TILs. Additionally, we discuss the emerging role of immunotherapy in breast cancer, and the future of TIL characterisation in this context.

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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