RESUMEN
Immune checkpoint (IC) blockade and adoptive transfer of tumor-specific T-cells (ACT) are two major strategies to treat metastatic melanoma. Their combination can potentiate T-cell activation in the suppressive tumor microenvironment, but the autoimmune adverse effects associated with systemic injection of IC blockers persist with this strategy. ACT of tumor-reactive T-cells defective for IC expression would overcome this issue. For this purpose, PD-1 and TIGIT appear to be relevant candidates, because their co-expression on highly tumor-reactive lymphocytes limits their therapeutic efficacy within the tumor microenvironme,nt. Our study compares the consequences of PDCD1 or TIGIT genetic deletion on anti-tumor properties and T-cell fitness of melanoma-specific T lymphocytes. Transcriptomic analyses revealed down-regulation of cell cycle-related genes in PD-1KO T-cells, consistent with biological observations, whereas proliferative pathways were preserved in TIGITKO T-cells. Functional analyses showed that PD-1KO and TIGITKO T-cells displayed superior antitumor reactivity than their wild-type counterpart in vitro and in a preclinical melanoma model using immunodeficient mice. Interestingly, it appears that TIGITKO T-cells were more effective at inhibiting tumor cell proliferation in vivo, and persist longer within tumors than PD-1KO T-cells, consistent with the absence of impact of TIGIT deletion on T-cell fitness. Taken together, these results suggest that TIGIT deletion, over PD-1 deletion, in melanoma-specific T-cells is a compelling option for future immunotherapeutic strategies.
Asunto(s)
Melanoma , Receptor de Muerte Celular Programada 1 , Receptores Inmunológicos , Animales , Ratones , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Melanoma/inmunología , Melanoma/genética , Melanoma/patología , Melanoma/terapia , Eliminación de Gen , Microambiente Tumoral/inmunología , Ratones Noqueados , Ratones Endogámicos C57BL , Linfocitos T/inmunología , Linfocitos T/metabolismo , Línea Celular Tumoral , Humanos , Activación de Linfocitos/inmunologíaRESUMEN
The 24th edition of the annual NAT conference (Nantes Actualités Transplantation) and the 4th edition of the biennial LabEx IGO meeting (Immunotherapy Graft Oncology) were held jointly around a common theme: "New horizons in immunotherapy", on May 31st and June 1st 2021 to highlight new findings in the fields of transplantation, autoimmunity and cancer.