Low-Dose Irradiation Programs Macrophage Differentiation to an iNOS+/M1 Phenotype that Orchestrates Effective T Cell Immunotherapy
Menée à l'aide de xénogreffes sur des modèles murins, cette étude met en évidence un mécanisme par lequel une faible dose de rayonnements gamma permet, via la différenciation des macrophages tumoraux en macrophages exprimant l'inosine monophosphate déshydrogénase et l'antigène M1, de modifier le micro-environnement de la tumeur et d'améliorer l'efficacité d'une immunothérapie basée sur le recrutement des lymphocytes T spécifiques
Inefficient T cell migration is a major limitation of cancer immunotherapy. Targeted activation of the tumor microenvironment may overcome this barrier. We demonstrate that neoadjuvant local low-dose gamma irradiation (LDI) causes normalization of aberrant vasculature and efficient recruitment of tumor-specific T cells in human pancreatic carcinomas and T-cell-mediated tumor rejection and prolonged survival in otherwise immune refractory spontaneous and xenotransplant mouse tumor models. LDI (local or pre-adoptive-transfer) programs the differentiation of iNOS+ M1 macrophages that orchestrate CTL recruitment into and killing within solid tumors through iNOS by inducing endothelial activation and the expression of TH1 chemokines and by suppressing the production of angiogenic, immunosuppressive, and tumor growth factors. "Local LDI efficiently recruits effector T cells into tumors"LDI enables efficient T-cell-mediated tumor rejection and improved survival"LDI acts through iNOS induction in tumor-associated macrophages"INOS raises TH1 chemokines and inhibits angiogenic and immune suppressive cytokines