Tissue-resident memory T cells in the era of (Neo) adjuvant melanoma management

Abstract

Tissue-resident memory T (TRM) cells have emerged as key players in the immune control of melanoma. These specialized cells are identified by expression of tissue retention markers such as CD69, CD103 and CD49a with downregulation of egress molecules such as Sphingosine-1-Phosphate Receptor-1 (S1PR1) and the lymphoid homing receptor, CD62L. TRM have been shown to be integral in controlling infections such as herpes simplex virus (HSV), lymphocytic choriomeningitis virus (LCMV) and influenza. More recently, robust pre-clinical models have also demonstrated TRM are able to maintain melanoma in a dormant state without progression to macroscopic disease reminiscent of their ability to control viral infections. The discovery of the role these cells play in anti-melanoma immunity has coincided with the advent of immune checkpoint inhibitor (ICI) therapy which has revolutionized the treatment of cancers. ICIs that target programmed death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) have led to substantial improvements in outcomes for patients with metastatic melanoma and have been rapidly employed to reduce recurrences in the resected stage III setting. While ICIs mediate anti-tumor activity via CD8+ T cells, the specific subsets that facilitate this response is unclear. TRM invariably exhibit high expression of immune checkpoints such as PD-1, CTLA-4 and lymphocyte activating gene-3 (LAG-3) which strongly implicates this CD8+ T cell subset as a crucial mediator of ICI activity. In this review, we present pre-clinical and translational studies that highlight the critical role of TRM in both immune control of primary melanoma and as a key CD8+ T cell subset that mediates anti-tumor activity of ICIs for the treatment of melanoma.

Heterogeneity and plasticity of tissue-resident memory T cells in skin diseases and homeostasis: a review

“…Further support for circulating Trm cell precursors was provided by a study on Trm cell formation, in which CD127, which is present in humans and is the α chain of IL-7R, was identified. The interaction between IL-7 and CD127 plays an important role in the differentiation and maintenance of T-cell homeostasis ( 37 ). It is highly expressed in various autoimmune and inflammatory skin diseases.…”

“…They have a protective effect on the skin and can be maintained for an extended period. However, it is worth mentioning that the expression of the immune checkpoints PDCD1, LAGLA3, and TIGIT is higher in tumor-specific Trm cells than in Tcm cells or Tem cells ( 37 ). CD8 + CD69 + CD103 + Trm cells also showed higher PD-1 and lag3 immune checkpoint expression than CD8 + CD69 - CD103 - cells.…”

“…The constitutive expression of CTLA-4 suppresses T-cell-mediated immune responses in response to chronic TCR stimulation by infection or malignancy ( 90 ). However, the role of this critical checkpoint in Trm cell function remains unclear ( 37 ).…”

A phase 2 trial of peri-operative avelumab and chemotherapy for locally advanced gastro-esophageal adenocarcinoma: Association of AGR2/AP-1 complex CD8 T-cells and M2-Tumour Associated Macrophages with treatment response

“…Studies have suggested that neoadjuvant systemic therapy modulates the number of CD8+ memory T cells with some suggestion that greater in ltration is associated with better disease response 51,52 . Furthermore, data in the setting of melanoma has shown this subset of T cells to richly exhibit checkpoint inhibitors and thus mediate response to immunotherapy 53 .…”

Functional heterogeneity of human skin‐resident memory T cells in health and disease

“…Importantly, CD69 + CD103 + tumor‐resident CD8 + T cells and local IL‐15 production were associated with response to immune checkpoint inhibitors 139 . CD8 + T RM exhibit high levels of PD‐1, CTLA‐4, and LAG‐3, and a recent review is dedicated to their crucial role in melanoma immunotherapy 152 . Conversely, CD69 + CD103 + T RM exhibited increased IL‐10 production in cutaneous squamous cell carcinoma, a common non‐melanoma skin cancer (NMSC), probably representing an exhausted dysfunctional T‐cell subset 153,154 .…”