Tissue-resident memory T cells in gastrointestinal cancer immunology and immunotherapy: ready for prime time?

Abstract

Tissue-resident memory T (T_RM) cells have emerged as immune sentinels that patrol the tissue microenvironment and orchestrate localized antitumor immunity in various solid cancers. Recent studies have revealed that T_RM cells are key players in cancer immunosurveillance, and their involvement has been linked to favorable responses to immunotherapy as well as general better clinical outcome in cancer patients. In this review, we provide an overview of the major advances and recent findings regarding T_RM cells phenotype, transcriptional and epigenetic regulation in cancer with a special focus on gastrointestinal tumors. Finally, we highlight the exciting clinical implication of T_RM cells in these types of tumors.

Keywords: gastrointestinal neoplasms; immunity; immunologic memory; immunotherapy.

Figure 1

Summary of the most upregulated/ downregulated genes in T_RM cells identified by Bulk/Sc-RNA sequencing. This spin chart summarizes the core residency signature specific to T_RM cells compared with T_EM and T_CM identified by bulk and/or single-cell analysis. T_RM signature is mainly characterized by high expression of genes encoding for tissue residency and immune checkpoints (in red), both quite tissue-specific, in this figure, we also focused on those GI cancers specific such as CD103, CXCR6, PD-1, and LAG-3. Another remarkable feature of T_RM cells signature is the upregulated expression of cytotoxicity and functionality encoding genes compared with their memory counterparts T_EM and T_CM. Along with this upregulation, certain genes signaling are either completely shut down (in blue) such as tissue egress ones (SELL, CCR7) and TCF1 which inhibit ITGAE (CD103) expression or downregulated such as TBX21 (T-bet) for IL-15R expression maintenance. GI, gastrointestinal; T_CM, central memory T cells; T_EM, effector memory T cells; T_RM, tissue-resident memory T cells.

Figure 2

Phenotypic heterogeneity of CD8 T_RM cells across cancer types. An overview of the reported CD8 T_RM cells phenotype in GI and non-GI cancers showing an inter and intra-organ heterogeneity. HNSCC, head and neck squamous cell carcinomas; GI, gastrointestinal; PDAC, pancreatic ductal adenocarcinoma.

Figure 3

From Zero to Hero: T_RM cells in the cancer-immunity cycle. (A) T_RM cells precursors are primed in the tumor-draining lymph node by DCs. (B) Once in the tumor microenvironment and in the presence of TGF-β and IL-15, T_RM cells precursors will differentiate into T_RM cells. Induction of a core residency signature such as expression of tissue retention molecules (CD103, CD69, CD49a, CXCR6) and acquisition of high cytotoxic activity (GZMB, perforin) is under epigenetic regulation and key transcription factors instructions (Blimp1, Hobit, Runx3, Bhlhe40, and Notch). (C) Once fully differentiated, tumor-specific T_RM cells can enact cancer cells eradication via an arsenal of cytotoxic molecules such as perforin and granzyme. CD103 expression enables T_RM cells biding to E-cadherin expressing tumor cells which sustains the immunological synapse, hence triggering lytic granules polarization and exocytosis. DC, dendritic cell; T_RM, tissue-resident memory T cells.

Figure 4

T_RM cells as a tool for GI cancers immunotherapy. T_RM cells are emerging as long persisting potent cytotoxic T cells destined for tissue residency, making them a hot target for cancer immunotherapy in general and GI cancers in particular. This is a representation of the potential therapeutic strategies where T_RM cells could be incorporated into GI cancers standard treatment paradigms. For immune infiltrated or the so-called ‘hot’ GI tumors, T_RM cells could serve as a predictive factor as well as a target for checkpoint inhibitors. For the therapeutically challenging ‘cold’ GI tumors, in vitro expanded or generated CXCR6⁺ tumor-specific T_RM cells could be adoptively transferred in combination or not with checkpoint inhibitors. GI, gastrointestinal; T_RM, tissue-resident memory T cells.