The potential role of CD8+ cytotoxic T lymphocytes and one branch connected with tissue-resident memory in non-luminal breast cancer

Abstract

Advances in understanding the pathological mechanisms of breast cancer have resulted in the emergence of novel therapeutic strategies. However, triple-negative breast cancer (TNBC), a molecular subtype of breast cancer with a poor prognosis, lacks classical and general therapeutic targets, hindering the clinical application of several therapies to breast cancer. As insights into the unique immunity and molecular mechanisms of TNBC have become more extensive, immunotherapy has gradually become a valuable complementary approach to classical radiotherapy and chemotherapy. CD8+ cells are significant actors in the tumor immunity cycle; thus, research on TNBC immunotherapy is increasingly focused in this direction. Recently, CD8+ tissue-resident memory (TRM) cells, a subpopulation of CD8+ cells, have been explored in relation to breast cancer and found to seemingly play an undeniably important role in tumor surveillance and lymphocytic infiltration. In this review, we summarize the recent advances in the mechanisms and relative targets of CD8+ T cells, and discuss the features and potential applications of CD8+ TRM cells in non-luminal breast cancer immunotherapy.

Keywords: Breast cancer; CD8+ T cells; Immunotherapy; Tissue-resident memory T cell; Triple negative breast cancer.

Figure 1. CAR-T therapy has played a good role in anti-tumor, with more direct and immediate cytotoxicity. CAR-T associated with CD8+ T cells can be programmed with different plug-in components.

Among them, extracellular single-stranded variable fragments (scFv) can be specifically constructed in vitro to target breast cancer by contact with tumor-associated antigens (TAAs). The intracellular components are continuously innovated to enhance the comprehensive capabilities of engineered CD8+ T cells. In addition, some suicide genes have been incorporated into the design to avoid detumorization effects. Created with Biorender.com.

Figure 2. Correlation between CD8+T cell and other immune cells.

Following presentation of tumor antigens by specific antigen-presenting cells (APCs), CD8+ T cells produce an immune response to tumor cells involved in cytokines. In breast cancer, in addition to the positive anti-tumor effects, there are some cases of T cell failure caused by a negative immunosuppressive process mediated by tumor cells through immune checkpoints. NK, natural killer; DC, dendritic cells. Created with Biorender.com.

Figure 3. CD8+ TRM cell.

Figure 3 CD8+ TRM has a more powerful and rapid attack on tumor cells than ordinary CD8+ T cells, and future applications in breast cancer should focus on how to target to increase the efficiency and quantity of TRM as a tumor suppressor. In addition to the various targets of TRM synergistic localization, adhesion and killing of tumor cells, there are also some significant cytokines that can directly or indirectly induce CD8+ T cells to differentiate into CD8+ TRM, such as TGF-β produced by cDC1. In addition, immune checkpoints often mediate self-monitoring and management of TRM, which may be interfered with by immune checkpoint blockers (ICBs) and metabolic regulation to better utilize fatty acids (fas) against tumor cells. Created with Biorender.com.