Targeting Resident Memory T Cells for Cancer Immunotherapy

Abstract

A novel population of memory CD8+ T cells called resident memory T cells (TRM) has been identified based on their phenotype (CD103, CD69) and on their local tissue residency without recirculating in the blood. These cells have been implicated in protective immune response against pathogens in both animal models and humans. Their role in cancer is just emerging as a key player in tumor immunosurveillance. Many properties of these cells suggest that they could control tumor growth: (i) they respond much faster to reexposure to cognate antigen than circulating memory cells, (ii) they express high levels of cytotoxic molecules, and (iii) they are enriched in tumor-specific T cells in close contact with tumor cells. TRM are present in many human cancers and are associated with a good clinical outcome independently of the infiltration of CD8+ T cells. It has been recently shown that the efficacy of cancer vaccines depends on their ability to elicit TRM. In adoptive cell therapy, the transfer of cells with the ability to establish TRM at the tumor site correlates with the potency of this approach. Interestingly, TRM express immune checkpoint molecules and preliminary data showed that they could expand early during anti-PD-1 treatment, and thus be considered as a surrogate marker of response to immunotherapy. Some cues to better expand these cells in vivo and improve the success of cancer immunotherapy include using mucosal routes of immunization, targeting subpopulations of dendritic cells as well as local signal at the mucosal site to recruit them in mucosal tissue.

Immunity, Hypoxia, and Metabolism–the Ménage à Trois of Cancer: Implications for Immunotherapy

“…T RM are characterized by CD69 and CD103 expression, respond faster to antigen re-exposure and have a superior cytotoxic capacity than other types of memory T cells (10,326). In the clinical arena, using memory CTLs instead of naïve or effector CTLs holds promise for an improved and longlasting anti-tumor effect that locally protects from recurrence (10,57).…”

“Re-educating” Tumor Associated Macrophages as a Novel Immunotherapy Strategy for Neuroblastoma

“…In recent years, immune checkpoint blockade has demonstrated that targeting the immune system by activating previously exhausted or dysfunctional T cells can lead to long-term control of various cancers, including melanoma ( 57 – 59 ). In particular, cytotoxic CD8+ T cells are important for tumor cell killing and memory CD8+ T cells are important for durable anti-tumor immunity ( 60 ). However, many tumors, including neuroblastoma and other pediatric tumors, do not respond or have limited response to CTLA-4 and PD-1/Programmed death-ligand 1 (PD-L1) blockade ( 32 , 33 ), and studies have found mechanisms of resistance, including poor infiltration of T cells, tumor cells that lack response to interferon-γ (IFN-γ), and immunosuppressive cell populations in the tumor microenvironment ( 61 ).…”

Resident Memory T Cells and Their Effect on Cancer

“…T RM cells were quantified using quantitative multiplex immunofluorescence staining to show that the presence of T RM cells in immunotherapy-naïve melanoma samples was associated with significantly increased melanoma-specific survival, and this cell population was further expanded using anti-PD-1 therapy [23]. Additionally, Blanc et al showed that the T RM cell population increases within tumors during the early stages of anti-PD-1 treatment [41]. In addition, T RM cells isolated from lung carcinomas co-cultured with autologous tumor cells demonstrate enhanced cytotoxic activity in the presence of PD-1 targeting antibodies compared to those not treated with PD-1 antibodies [9].…”