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Tissue-resident memory T cells in breast cancer control and immunotherapy responses

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.

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Fig. 1: The potential role of TRM cells in antitumour immunity.

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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).

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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

Correspondence to Sherene Loi.

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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.

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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.

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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

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