ReviewTissue-resident memory-like T cells in tumor immunity: Clinical implications
Introduction
Immune system consists of both innate as well as adaptive components with potent capacity to control tumors. Success of therapies that block inhibitory immune checkpoints on T cells, as well as therapies that redirect T cells (such as via chimeric-antigen receptors (CAR), or bispecific antibodies), have transformed clinical oncology and placed T cells at the center of immune-mediated approaches to battle cancer [1]. An important aspect of T cell immunity is the property of immunologic memory, which is essential for long term protection [2]. Tissue-resident memory (TRM) T cells are a phenotypically and transcriptionally distinct population of non-recirculating memory T cells that reside within non-lymphoid tissue and provide regional protection against pathogens and tumors in several models [3,4]. In this review, we discuss emerging insights about the biology of these cells in the setting of cancer with a particular focus on human TRM cells and the implications of recent studies on TRMs for harnessing tumor immunity in the clinic.
Section snippets
Lessons from mice
TRM cells have been classically identified as non-recirculating T cells that reside and renew within tissues and do not equilibrate with circulating T cell pool. In mice, TRM compartment has been studied using various approaches including parabiosis [5,6], transplantation [7,8], intravascular labeling [9,10] and targeted antibody-mediated T cell depletion [4]. While the majority of studies have focused on CD8 + TRM cells, the presence of CD4+ TRM cells has also been characterized in both humans
Evidence for human TRM T cells
As experimental parabiosis is not feasible in the human setting, evidence for equivalent tissue-localized T cells in humans has been based on finding T cells that persist in tissues following organ transplantation or antibody-mediated depletion of circulating T cells. HLA-mismatched TRM cells can persist long term in patients following lung and bowel transplants [[36], [37], [38]]. Administration of anti-CD52 antibody (alemtuzumab) depletes circulating T cells without concurrent depletion of
Preclinical studies for anti-tumor potential of TRM cells
Potential role for TRM cells in tumor immunity first emerged from studies showing TRM phenotype of T cells infiltrating human tumors [44,45], but their anti-tumor properties and role in immune surveillance has now been demonstrated in the context of murine models as well [46,47]. Mice lacking molecules expressed on TRM cells such as CD69 or CD103 are more susceptible to transplantable melanoma than wild-type mice [46,47]. TRM cells generated by vaccination mediate protection against tumor
Mechanisms of anti-tumor effects of TRM cells
The mechanisms by which TRM cells mediate anti-tumor effects remain to be fully clarified and may differ in specific settings and tumor type. CD103 expressed on some TRM cells may promote immunologic synapse by binding to E-cadherin on tumor cells [51,52]. A major mechanism of TRM-mediated control may be via non-cytotoxic mechanisms and mediated in part by cytokines such as TNF [47]. In this regard, TRM cells may act more as controllers than as killers, similar to their role in control of
Generation and maintenance of TRM T cells within tumors
Information about the generation of intra-tumoral TRM-like T cells is more limited compared to that for virus-specific T cells. Subsets of intra-tumoral T cells in human tumors express Hobit, but its role in biology of human TRM-like cells is not clear. Lineage tracing and single cell transcriptomic studies have identified subsets of circulating effector cells as precursors with greater potential for TRM generation in tumor models [55,56]. TGFβ is abundant in many tumors and could regulate TRM
TRM-like T cells in human tumors
It is now well recognized that tumors are commonly infiltrated by heterogeneous populations of lymphocytes that include both innate and adaptive immune cells. Several studies have now demonstrated that a proportion of tumor-infiltrating lymphocytes (TILs) in human tumors express surface markers (e.g. CD69) or molecular signatures consistent with tissue resident memory T cells [44,45,58,61,62]. CD69 expression can in principle also be induced by cognate antigen stimulation, although the genomic
Non-uniform regional immunity and inter-lesional heterogeneity
It is increasingly appreciated that degree of T cell infiltration within tumors is associated with improved outcome, occasionally in the absence of detectable circulating tumor-specific T cells, which points to the importance of regional immunity in cancer. However, the degree to which this regional immunity remains localized to the tumor lesion or whether it has considerable systemic component has broad implications not just for measuring and harnessing immune responses in the clinic but also
TRM cells as targets to improve cancer vaccines
The field of cancer vaccines is replete with examples wherein vaccine-induced systemic or circulating T cell responses do not correlate with protective immunity or tumor regressions in the clinic. Based on the considerations discussed earlier, it is tempting to speculate that an important missing link may be the inability of current vaccines to effectively enhance TRM cells within tumors. Mucosal vaccination protocols that lead to greater generation of TRM cells mediate greater protection than
TRM cells as targets of immune checkpoint blockade
Blockade of immune checkpoints such as PD-1 has transformed immune therapy of human cancer. However, these checkpoints are expressed on only a subset of T cells within human tumors. Several studies have shown that T cells with TRM phenotype and genomic signatures are the subset of tumor-infiltrating T cells with highest level of expression of inhibitory immune checkpoints within human tumors [45,61], raising the possibility that TRM cells are an important target of immune checkpoint blockade,
TRM cells as targets of adoptive cell therapies
The ability of adoptively transferred T cells to infiltrate into tumors and persist long term have emerged as essential characteristics for effective therapy. These features are also imprinted into the biology of TRM cells. Adoptive transfer of tumor infiltrating lymphocytes, which contain a variable but high proportion of TRM cells, has been shown to mediate tumor regression in patients with melanoma and renal cell cancer [101]. Indeed, among TILs, tumor-specific T cells were shown to express
Summary
Cells with phenotype and genomic signatures of tissue-resident memory T cells have been identified in several human tumors, wherein they correlate with outcome and response to immune therapy [35,69]. Anti-tumor effects of these T cells have also been demonstrated in preclinical models. TRM biology has profound implications for how to optimally engage and enhance tumor immunity in the clinic. However, several questions relating to their generation, heterogeneity, tissue residence, maintenance
Acknowledgements
KMD is supported in part by funds from the NIH (RO1CA238471 and RO1AR077926) and SCOR award from the Leukemia and Lymphoma Society. MVD is supported in part by funds from the NIH (R35CA197603) and SCOR award from the Leukemia and Lymphoma Society.
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