Transcriptional repression by HDAC3 mediates T cell exclusion from mutant lung tumors.
Caroline K McGuire, Ambryn S Meehan, Evan Couser, Lois Bull, Allegra C Minor, Alexandra Kuhlmann-Hogan, Susan M Kaech, Reuben J Shaw, Lillian J Eichner
Author Information
Caroline K McGuire: Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL 60611.
Ambryn S Meehan: Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL 60611.
Evan Couser: Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL 60611.
Lois Bull: Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL 60611.
Allegra C Minor: Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL 60611.
Alexandra Kuhlmann-Hogan: NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037.
Susan M Kaech: NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037. ORCID
Reuben J Shaw: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla CA 92037. ORCID
Lillian J Eichner: Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL 60611. ORCID
Histone Deacetylase 3 (HDAC3) function in vivo is nuanced and directed in a tissue-specific fashion. The importance of HDAC3 in 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 mutant lung cancer cells, we found that HDAC3 is a direct transcriptional repressor of a cassette of secreted chemokines, including . Genetic and pharmacological inhibition of HDAC3 robustly up-regulated this gene set in human and mouse , (KL) and , (KP) mutant lung cancer cells through an NF-��B/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 . Furthermore, we found that inhibition of HDAC3 in the presence of Kras pathway inhibitors dissociated 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 mutant lung tumors.
