Tissue-resident memory T cells in tumor immunity and immunotherapy

Abstract

Tissue-resident memory T cells (TRM) represent a heterogeneous T cell population with the functionality of both effector and memory T cells. TRM express residence gene signatures. This feature allows them to traffic to, reside in, and potentially patrol peripheral tissues, thereby enforcing an efficient long-term immune-protective role. Recent studies have revealed TRM involvement in tumor immune responses. TRM tumor infiltration correlates with enhanced response to current immunotherapy and is often associated with favorable clinical outcome in patients with cancer. Thus, targeting TRM may lead to enhanced cancer immunotherapy efficacy. Here, we review and discuss recent advances on the nature of TRM in the context of tumor immunity and immunotherapy.

Figure 1.

T_RM in tumor immunity. (1 and 2) Before specific antigen priming, CD8⁺ naive T cells may interact with DCs in the presence of TGF-β. This process may prepare T_RM formation. (3) During memory phase, T_SCM may give rise to different memory subsets, including T_RM. IL-2, IL-15, and TGF-β, which may provide optimal signaling for T_RM formation. (4) T_RM precursors may undergo a transcription factor–driven generation program. (5) T_RM can traffic into the tumor microenvironment, and they are maintained in situ without (or with minimal) recirculation. (6) T_RM retention in tumors may be related to certain integrins, including CD44, α1(CD49a)β1, αE(CD103)β7, and CD69. CD44 and α1(CD49a)β1 tether T_RM to the extracellular matrix. αE(CD103)β7 anchors T_RM via interacting with E-cadherin on the epithelial cell surface. CD69 blocks S1PR1-mediated “exit” signaling. Blockade of T_RM egress from the tissue may be promoted by up-regulation of some transcription factors (including Blimp, Hobit, Notch, and Runx) and by down-regulation of Krüppel-like factor 2 (KLF2). Microbiome-derived SCFA may promote long-term maintenance of T_RM. FABP and FFA uptake may favor T_RM survival and antitumor functionality. T_RM may express immune checkpoint proteins, suggesting that T_RM likely responds to checkpoint blockade. (7) T_RM may release perforin and GzmB and directly kill target tumor cells. T_RM-derived cytokines (IFN-γ, IL-2, and TNF-α) promote infiltration of DCs, T and B cells, and natural killer cells, indirectly boosting antitumor immunity.

Figure 2.

T_RM in cancer immunotherapy. Several strategies have been proposed to enhance T_RM activity. Checkpoint blockade may enhance intratumoral proliferation of T_RM. DCs may be used as a vaccine to induce functional T_RM. Targeting specific transcription factors and cytokines may drive T_RM formation and may boost induction of active T_RM. Targeting particular metabolites (e.g., FFA and FABP) may promote T_RM pool and antitumor activity. Adoptive transfer of preprogramed T_RM or T_SCM may improve T_RM seeding or differentiation, thereby enhancing antitumor immunity. PPAR, peroxisome proliferator–activated receptor.