Abstract
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.
| Original language | English (US) |
|---|---|
| Article number | e2317694121 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 121 |
| Issue number | 42 |
| DOIs | |
| State | Published - Oct 15 2024 |
Funding
molecular phenotyping services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory (MHPL) which is supported by NCI P30-CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. We thank Dr. Bin Zhang at Northwestern University for the recommendation of the Proteome Profiler Mouse XL Cytokine Array. ACKNOWLEDGMENTS. At the Salk Institute for Biological Studies, L.J.E. was supported by a postdoctoral fellowship from the American Cancer Society (PF-15-037-01-DMC). At Northwestern University, research reported in this publication was supported by Grants to L.J.E. from the National Cancer Institute of the NIH (K22CA251636), an American Cancer Society Institutional Research Grant (IRG-21-144-27), a Mission Boost Grant Stage I (MBGI-23-1031644-01-MBG) from the American Cancer Society, aChuck Maniscalco Grant of Hope Research Scholar Grant (RSG-23-1031646-01-DMC) from the American Cancer Society, a V Scholar Grant (V2023-019) from the V Foundation for Cancer Research with support from the Orr Family Foundation, an IDP Foundation Research Innovation Challenge Award, and the Robert H. Lurie At the Salk Institute for Biological Studies, L.J.E. was supported by a postdoctoral fellowship from the American Cancer Society (PF-15-037-01-DMC). At Northwestern University, research reported in this publication was supported by Grants to L.J.E. from the National Cancer Institute of the NIH (K22CA251636), an American Cancer Society Institutional Research Grant (IRG-21-144-27), a Mission Boost Grant Stage I (MBGI-23-1031644-01-MBG) from the American Cancer Society, aChuck Maniscalco Grant of Hope Research Scholar Grant (RSG-23-1031646-01-DMC) from the American Cancer Society, a V Scholar Grant (V2023-019) from the V Foundation for Cancer Research with support from the Orr Family Foundation, an IDP Foundation Research Innovation Challenge Award, and the Robert H. Lurie Comprehensive Cancer Center. This study was supported by Grants to R.J.S. from the NIH (R35CA220538 and P01CA120964) and The Leona M. and Harry B. Helmsley Charitable Trust Grant #2012-PG- MED002. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was supported by the NGS and the Razavi Newman Integrative Genomics and Bioinformatics Core Facilities of the Salk Institute with funding from the NIH-NCI CCSG: P30 014195, the Chapman Foundation, and the Helmsley Charitable Trust. Tissue Technology Shared Resource is supported by a National Cancer Institute Cancer Center Support Grant (CCSG Grant P30CA23100). Non-clinical research histopathology and molecular phenotyping services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory (MHPL) which is supported by NCI P30-CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. We thank Dr. Bin Zhang at Northwestern University for the recommendation of the Proteome Profiler Mouse XL Cytokine Array. Comprehensive Cancer Center. This study was supported by Grants to R.J.S. from the NIH (R35CA220538 and P01CA120964) and The Leona M. and Harry B. Helmsley Charitable Trust Grant #2012-PG-MED002. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was supported by the NGS and the Razavi Newman Integrative Genomics and Bioinformatics Core Facilities of the Salk Institute with funding from the NIH-NCI CCSG: P30 014195, the Chapman Foundation, and the Helmsley Charitable Trust. Tissue Technology Shared Resource is supported by a National Cancer Institute Cancer Center Support Grant (CCSG Grant P30CA23100). Non-clinical research histopathology and
Keywords
- Histone Deacetylase 3
- KRAS mutant lung cancer
- NF-κB p65
- T cell recruitment
- tumor immune microenvironment
ASJC Scopus subject areas
- General
