Resident memory T cells, critical components in tumor immunology

Abstract

CD8+ T lymphocytes are the major anti-tumor effector cells. Most cancer immunotherapeutic approaches seek to amplify cytotoxic T lymphocytes (CTL) specific to malignant cells. A recently identified subpopulation of memory CD8+ T cells, named tissue-resident memory T (TRM) cells, persists in peripheral tissues and does not recirculate. This T-cell subset is considered an independent memory T-cell lineage with a specific profile of transcription factors, including Runx3+, Notch+, Hobit+, Blimp1+, BATF+, AHR+, EOMESneg and Tbetlow. It is defined by expression of CD103 (αE(CD103)β7) and CD49a (VLA-1 or α1β1) integrins and C-type lectin CD69, which are most likely involved in retention of TRM cells in non-lymphoid tissues, including solid tumors. CD103 binds to the epithelial cell marker E-cadherin, thereby favoring the location and retention of TRM in epithelial tumor regions in close contact with malignant cells. The CD103-E-cadherin interaction is required for polarized exocytosis of lytic granules, in particular, when ICAM-1 expression on cancer cells is missing, leading to target cell death. TRM cells also express high levels of granzyme B, IFNγ and TNFα, supporting their cytotoxic features. Moreover, the local route of immunization targeting tissue dendritic cells (DC), and the presence of environmental factors (i.e. TGF-β, IL-33 and IL-15), promote differentiation of this T-cell subtype. In both spontaneous tumor models and engrafted tumors, natural TRM cells or cancer-vaccine-induced TRM directly control tumor growth. In line with these results, TRM infiltration into various human cancers, including lung cancer, are correlated with better clinical outcome in both univariate and multivariate analyses independently of CD8+ T cells. TRM cells also predominantly express checkpoint receptors such as PD-1, CTLA-4 and Tim-3. Blockade of PD-1 with neutralizing antibodies on TRM cells isolated from human lung cancer promotes cytolytic activity toward autologous tumor cells. Thus, TRM cells appear to represent important components in tumor immune surveillance. Their induction by cancer vaccines or other immunotherapeutic approaches may be critical for the success of these treatments. Several arguments, such as their close contact with tumor cells, dominant expression of checkpoint receptors and their recognition of cancer cells, strongly suggest that they may be involved in the success of immune checkpoint inhibitors in various cancers.

Immune infiltration in renal cell carcinoma

“…Here, we found that a high level of CD8+ T cells was associated with prolonged OS in KICH and that a high level of resting memory CD4+ T cells was associated with a better outcome in KIRC. Regarding subpopulations of T cells, CD8+ T cells are critical anti–tumor effector cells, while resting memory CD4+ T cells can differentiate further to possess various functions (eg, differentiate to CD8 + memory T cells to suppress tumor growth) . We observed a lower fraction of CD8+ T cells in KICH compared with KIRC and KIRP, suggesting that KICH might have an immune‐excluded phenotype where CD8+ T cells were maintained in the stroma, restricting cancer immunity.…”

“…T cells are critical anti-tumor effector cells, while resting memory CD4+ T cells can differentiate further to possess various functions (eg, differentiate to CD8 + memory T cells to suppress tumor growth). 31,32 We observed a lower fraction of CD8+ T cells in KICH compared with KIRC and KIRP, suggesting that KICH might have an immune-excluded phenotype where CD8+ T cells were maintained in the stroma, restricting cancer immunity. Interestingly, the infiltration of cytotoxic CD8+ T cells might be modified by immunotherapy.…”

The Immunoscore: Colon Cancer and Beyond

“…These findings encourage us to shift our focus from the classic location-or cytology-based prognosis to an immune-based one. In this scenario, the main characters associated with prolonged survival are the cytotoxic T cells, memory T cells, T H 1 cells, and the newly identified lineage of tissue-resident memory T (T RM ) cells (3,4,16,17).…”

Identification and validation of an immunogenic subtype of gastric cancer with abundant intratumoural CD103+CD8+ T cells conferring favourable prognosis

“…Intratumoural CD103 + CD8 + T cells are more functionally restored following PD-1 blockade in gastric cancer than CD103 − CD8 + T cells Previous studies have shown that CD103 + CD8 + T cells rather than CD103 − CD8 + T cells are promising targets for immune checkpoint inhibitors. 27 Consequently, we further examined whether CD103 + CD8 + T cells and CD103 − CD8 + T cells respond differently to PD-1 blockade in gastric cancer. Flow cytometry analysis showed that PD-1 blockade had a more profound effect on the effector molecule expression of CD103 + CD8 + T cells than on that of CD103 − CD8 + T cells (Fig.…”