Resident Memory-Like Tumor-Infiltrating Lymphocytes (TILRM): Latest Players in the Immuno-Oncology Repertoire

Abstract

Resident memory T cells (TRM) are a recently identified subset of long-lived memory T cells that are characterized in terms of their unique surface phenotype combined with a non-recirculating pattern of localization to non-lymphoid, peripheral tissues. TRM have quickly become a key area of focus in understanding immune responses to microbial infection in so-called “barrier” tissues, and appear to be particularly critical for protection against repeat exposure at the same site. More recently, tumor-infiltrating T cells with canonical TRM features are being identified in human cancers, in particular cancers of epithelial origin, and their presence is broadly found to be associated with favorable long-term prognosis. Moreover, recent studies have shown that these “resident memory-like” tumor-infiltrating lymphocytes (referred to herein as TILRM) are uniquely activated in melanoma patients undergoing PD-1 directed checkpoint blockade therapy. Accordingly, there is much interest at present regarding the biology of these cells and their precise role in anti-cancer immunity. Herein, we review the current state of the literature regarding TILRM with a specific emphasis on their specificity, origins, and relationship to conventional pathogen-specific TRM and speculate upon the way(s) in which they might contribute to improved prognosis for cancer patients. We discuss the growing body of evidence that suggests TILRM may represent a population of bona-fide tumor-reactive T cells and the attractive possibility of leveraging this cell population for future immunotherapy.

The Whole Body as the System in Systems Immunology

“…In fact, studies have shown that the expression of certain chemokines are positively correlated with the abundance of TILs and with postoperative survival in melanoma and colorectal cancer ( Kistner et al., 2017 ; Martinet et al., 2012 ). In addition, TILs expressing T RM marker CD103 have been shown to be enriched in tumor tissue, particularly in cancers of epithelial origin, and often correlate with improved patient survival ( Boddupalli et al., 2016 ; Djenidi et al., 2015 ; Edwards et al., 2018 ; Komdeur et al., 2017 ; Smazynski and Webb, 2018 ; Wang et al., 2016 ; Webb et al., 2015 ).…”

Characterization of tumour-infiltrating lymphocytes in a tumour rejection cynomolgus macaque model

“…It has been shown that a subset of memory T cells does not recirculate but is maintained in peripheral tissues. Increasing evidence indicates that such T RM cells accumulate in various human cancer tissues and constitute a substantial population of TILs 10 . Indeed, in this macaque model, CD69, a marker for T RM cells, was barely expressed in circulating CD4 + and CD8 + T cells but was expressed in 56% and 64% of CD4 + and CD8 + TILs, respectively (Fig.…”

“…Accumulating evidence indicates that a substantial population of CD8 + TILs are T RM -like cells 10 . These T RM cells have been identified by surface expression of CD103 and CD69 in both humans and mice.…”

“…It is becoming clear that TILs share phenotypic characteristics with tissue-resident memory T (T RM ) cells, a recently discovered lineage of T cells that remain in tissues without recirculating through the blood 9 . T RM -like TILs can be found in various human tumours and mouse models, and the presence of these TILs is associated with a favourable prognosis 10 .…”

Modulation of Determinant Factors to Improve Therapeutic Combinations with Immune Checkpoint Inhibitors

“…In mouse and human tumors, tumor-infiltrating CD8 T RM (referred as CD8 TIL RM ) can represent up to 30% of CD8 T cells [102,103]. The presence of tumor-infiltrating CD103 + T RM is associated with improved outcome or recurrence-free survival in many solid human cancers including melanoma, lung, ovarian, cervical, bladder, urothelial, and breast cancer [104].…”