Adaptive immunity programmes in breast cancer

Abstract

The role of the immune system in shaping cancer development and patient prognosis has recently become an area of intense focus in industry and academia. Harnessing the adaptive arm of the immune system for tumour eradication has shown great promise in a variety of tumour types. Differences between tissues, however, necessitate a greater understanding of the adaptive immunity programmes that are active within each tumour type. In breast cancer, adaptive immune programmes play diverse roles depending on the cellular infiltration found in each tumour. Cytotoxic T lymphocytes and T helper type 1 cells can induce tumour eradication, whereas regulatory T cells and T helper type 2 cells are known to be involved in tumour-promoting immunosuppressive responses. Complicating these matters, heterogeneous expression of hormone receptors and growth factors in different tumours leads to disparate, patient-specific adaptive immune responses. Despite this non-conformity in adaptive immune behaviours, encouraging basic and clinical results have been observed that suggest a role for immunotherapeutic approaches in breast cancer. Here, we review the literature pertaining to the adaptive immune response in breast cancer, summarize the primary findings relating to the breast tumour's biology, and discuss potential clinical immunotherapies.

Keywords: T cells; adaptive immunity; breast cancer; immunotherapy; neoantigens.

Figure 1

Evasion of T‐cell immune responses in breast cancer. Upon recognition of a tumour antigen, cytotoxic T lymphocytes (CTLs) clonally expand and move through the body in search of the associated antigen‐producing tumour cells to eradicate. This process is not always successful, as the tumour may evade the T‐cell response in a variety of ways including: (i) inappropriate localization in the breast cancer microenvironment, where the CTL is not capable of reaching the antigen‐producing tumour cell due to localization in the stroma or other region; (ii) immunoediting, which leads to a loss of antigen or HLA expression preventing the CTL from detecting the tumour cell; (iii) recruitment of immunosuppressive cells that express inhibitory ligands capable of suppressing CTL function; or (iv) expression of death ligands that can deactivate or kill otherwise functional T cells.

Figure 2

T‐cell subsets in breast cancer. T‐cell subsets in breast cancer can broadly be divided into three categories. CD8⁺ cytotoxic T lymphocytes are involved in the direct lysis of antigen‐positive tumour cells. CD4⁺ T helper cells exist along an axis of differentiation. T helper type 1 (Th1) ‐polarized cells can enhance CD8⁺ cytotoxic T‐cell activity and can also activate antigen‐presenting dendritic cell function leading to increased anti‐tumour immunity. Th2 cells do the opposite, suppressing dendritic cell function, and are capable of inhibiting CD8⁺ T‐cell activity. Finally CD4⁺ FOXP3⁺ regulatory T cells suppress CD8⁺ cytotoxic T‐lymphocyte function, aiding in immune evasion by the tumour. These cells are also capable of suppressing Th1 T helper cell function, further suppressing cytotoxic function.

Figure 3

T‐cell immunotherapy in breast cancer. Induction and maintenance of breast cancer‐targeted T‐cell immunity remains at the forefront of pre‐clinical and clinical development. Major approaches to treat breast cancers include: (a) Active Vaccination, in which antigenic tumour‐associated antigens are delivered (in the context of autologous dendritic cells, as peptide in adjuvant, or via a viral vector) to the patient, stimulating the in situ expansion of tumour‐reactive CD8⁺ T cells; (b) Adoptive Cell Transfer (ACT), in which tumour antigen‐specific T cells are either (i) selected and expanded in vitro for re‐infusion or (ii) generated from bulk CD8⁺ populations by genetic modification to induce the expression of tumour‐specific T‐cell receptors or chimeric antigen receptors; (c) Bispecific T‐cell Engagers (BiTEs), which are fusions of immunoglobulin domains with specificity for tumours (via a surface‐expressed antigen) and T cells (usually via engagement of CD3), leading to physical tethering of tumours and T cells and subsequent activation of effector activity by the CD8⁺ cells, regardless of their nominal antigen specificity; and (d) Checkpoint blockade therapy, which uses humanized antibodies (such as Pembrolizumab and Nivolumab) to block the expression of death receptors (PD‐1) on lymphocytes, protecting them from the deactivation effects or death receptor ligand (PD‐L1) expression on tumour cells, thereby extending the effector activity of infiltrating T cells.