Transcriptional repression by HDAC3 mediates T cell exclusion from Kras mutant lung tumors

Menée à l'aide notamment de modèles murins modifiés génétiquement, cette étude met en évidence un mécanisme par lequel l'histone désacétylase 3 réprime le recrutement des lymphocytes T dans les tumeurs pulmonaires avec mutation du gène Kras

Résumé en anglais

Lung cancer is the leading cause of cancer-related death in the United States, and KRAS is the most frequently mutated oncogene in lung cancer. However, KRAS mutant lung tumors acquire resistance to standard-of-care therapies, and improved understanding of the underlying tumor biology is warranted in order to improve therapeutic options for this patient population. We found that HDAC3 restrains a gene expression program in lung cancer cells that is functionally linked to T cell recruitment. Preclinical studies revealed that therapeutically impinging upon this pathway enhances T cell recruitment into Kras mutant lung tumors, which contribute to tumor growth control. Together, our study highlights a key role for tumor cell–intrinsic HDAC3 in regulation of the tumor immune microenvironment. Histone Deacetylase 3 (HDAC3) function in vivo is nuanced and directed in a tissue-specific fashion. The importance of HDAC3 in Kras mutant lung tumors has recently been identified, but HDAC3 function in this context remains to be fully elucidated. Here, we identified HDAC3 as a lung tumor cell–intrinsic transcriptional regulator of the tumor immune microenvironment. In Kras mutant lung cancer cells, we found that HDAC3 is a direct transcriptional repressor of a cassette of secreted chemokines, including Cxcl10. Genetic and pharmacological inhibition of HDAC3 robustly up-regulated this gene set in human and mouse Kras, LKB1 (KL) and Kras, p53 (KP) mutant lung cancer cells through an NF-κB/p65-dependent mechanism. Using genetically engineered mouse models, we found that HDAC3 inactivation in vivo induced expression of this gene set selectively in lung tumors and resulted in enhanced T cell recruitment at least in part via Cxcl10. Furthermore, we found that inhibition of HDAC3 in the presence of Kras pathway inhibitors dissociated Cxcl10 expression from that of immunosuppressive chemokines and that combination treatment of entinostat with trametinib enhanced T cell recruitment into lung tumors in vivo. Finally, we showed that T cells contribute to in vivo tumor growth control in the presence of entinostat and trametinib combination treatment. Together, our findings reveal that HDAC3 is a druggable endogenous repressor of T cell recruitment into Kras mutant lung tumors.