Tumor-resident memory T cells as a biomarker of the response to cancer immunotherapy

Abstract

Tumor-infiltrating lymphocytes (TIL) often include a substantial subset of CD8⁺ tissue-resident memory T (T_RM) cells enriched in tumor-specific T cells. These T_RM cells play a major role in antitumor immune response. They are identified on the basis of their expression of the CD103 (α_E(CD103)β₇) and/or CD49a (α₁(CD49a)β₁) integrins, and the C-type lectin CD69, which are involved in tissue residency. T_RM cells express several T-cell inhibitory receptors on their surface but they nevertheless react strongly to malignant cells, exerting a strong cytotoxic function, particularly in the context of blocking interactions of PD-1 with PD-L1 on target cells. These T_RM cells form stable conjugates with autologous tumor cells and interact with dendritic cells and other T cells within the tumor microenvironment to orchestrate an optimal in situ T-cell response. There is growing evidence to indicate that TGF-β is essential for the formation and maintenance of T_RM cells in the tumor, through the induction of CD103 expression on activated CD8⁺ T cells, and for the regulation of T_RM effector functions through bidirectional integrin signaling. CD8⁺ T_RM cells were initially described as a prognostic marker for survival in patients with various types of cancer, including ovarian, lung and breast cancers and melanoma. More recently, these tumor-resident CD8⁺ T cells have been shown to be a potent predictive biomarker of the response of cancer patients to immunotherapies, including therapeutic cancer vaccines and immune checkpoint blockade. In this review, we will highlight the major characteristics of tumor T_RM cell populations and the possibilities for their exploitation in the design of more effective immunotherapy strategies for cancer.

Keywords: CD103 integrin; biomarker; cancer immunotherapy; tumor microenvironment; tumor-resident memory T (TRM) cells.

Figure 1

Differentiation of T_RM in tissue. Priming and differentiation of naïve CD8⁺ T cells take place in the lymph node in contact with monocytes or dendritic cells (DC3) which promote the generation of CD8⁺ T_RM precursors. Through cytokines secretion such as IFN-γ or IL-21, CD4⁺ T cells help CD8⁺ T cells to be fully functional and influence the T_RM differentiation. Primed CD8⁺ T_RM precursor cells reach the inflamed sites where they differentiate into CD8⁺ T_RM. Within the tissue, several cellular components regulate and maintain T_RM cells: DC3 participate in positioning CD8⁺ T_RM cells in an immune niche and promote their survival, DC infiltrating tumors, tumor cells or epithelial cells express integrin α_vβ₆ and α_vβ₈ and transform LAP-TGF-β to active TGF-β. Active TGF-β maintains tissue residence of T_RM cells and initiates CD103 signaling leading to functional and cytotoxic T_RM cells. CD4⁺ T_RM cells have recently been identified and are also present in peripheral tissues and solid tumors where they secrete inflammatory cytokines such as IFN-γ, TNF-α or IL-2.