ATRX Alteration Contributes to Tumor Growth and Immune Escape in Pleomorphic Sarcomas

SIMPLE SUMMARY: There is still no efficient systemic treatment for pleomorphic sarcomas. This study shows that 1/4 of them have an ATRX alteration that diminishes the immune response. This phenotype is related to the inhibition of mast cell recruitment upon ATRX alteration, which could be targeted to adapt immunotherapy against pleomorphic sarcomas. ABSTRACT: Whole genome and transcriptome sequencing of a cohort of 67 leiomyosarcomas has been revealed ATRX to be one of the most frequently mutated genes in leiomyosarcomas after TP53 and RB1. While its function is well described in the alternative lengthening of telomeres mechanism, we wondered whether its alteration could have complementary effects on sarcoma oncogenesis. ATRX alteration is associated with the down-expression of genes linked to differentiation in leiomyosarcomas, and to immunity in an additional cohort of 60 poorly differentiated pleomorphic sarcomas. In vitro and in vivo models showed that ATRX down-expression increases tumor growth rate and immune escape by decreasing the immunity load of active mast cells in sarcoma tumors. These data indicate that an alternative to unsuccessful targeting of the adaptive immune system in sarcoma could target the innate system. This might lead to a better outcome for sarcoma patients in terms of ATRX status.