Prognostic and therapeutic role of tumor-infiltrating lymphocyte subtypes in breast cancer

Abstract

Increased levels of total tumor-infiltrating lymphocytes (TILs) are generally associated with good prognosis in several breast cancer subtypes. Subtypes of TILs impact both tumor cells and immune cells in a variety of different ways, leading to either a pro-tumor or antitumor effect. Tumor-infiltrating CD8⁺ T cells and natural killer (NK) cells perform as effector cells against tumor cells and are associated with better clinical outcome. Immunotherapy approaches that improve the antitumor activity and proliferation of CD8⁺ T and NK cells include PD-1/PD-L1 blockade, CAR T cell therapy, or ex vivo-stimulated NK cells. A subset of CD8⁺ T cells, tissue-resident memory T cells, has also recently been associated with good prognosis in breast cancer patients, and has potential to serve as a predictive biomarker and therapeutic target. Tumor-infiltrating B cells also secrete apoptosis-inducing IgG antibodies and can act as antigen-presenting cells to prime CD4⁺ and CD8⁺ T cells. On the other hand, regulatory T and regulatory B cells modulate the immune response from CD8⁺ T cells and NK cells by secreting immunosuppressive cytokines and inhibiting maturation of antigen-presenting cells (APCs). These regulatory cells are typically associated with poor prognosis, therefore rendering suppression of their regulatory function a key immunotherapeutic strategy.

Keywords: Breast cancer; Immunotherapy; T cells; TILs; Tumor microenvironment.

Fig. 1

Tumor-infiltrating lymphocyte subsets in the tumor microenvironment (TME). (I) Naïve CD8⁺ T cells become activated upon binding to antigen-presenting dendritic cells (DCs) in the lymph nodes. Once activated, CD8⁺ effector T cells recognize and bind to tumor cells, inducing apoptosis via granzyme release. (II) Regulatory T cells inhibit the antitumor immune response by secreting immunosuppressive cytokines and restricting the activity of DCs by the binding of CTLA-4 to CD80/86 on DCs. (III) NK cells recognize tumor cells as ‘non-self’ and bind to induce apoptosis by releasing granzymes into the cell, as well as secrete immunostimulatory cytokines that recruit CD8⁺ effector T cells into the TME. (IV) B cells secrete tumor antigen-specific IgG antibodies that lead to apoptosis upon binding to the tumor, but B cells can also secrete immunosuppressive cytokines like TGF-β, IL-10, and IL-35 that promote tumor growth. Figure not drawn to scale. Created with BioRender.com