KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance
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Lung cancer treatment has benefited greatly through advancements in immunotherapies. However, immunotherapy often fails in patients with specific mutations like KEAP1, which are frequently found in lung adenocarcinoma. We established an antigenic lung cancer model and used it to explore how Keap1 mutations remodel the tumor immune microenvironment. Using single-cell technology and depletion studies, we demonstrate that Keap1-mutant tumors diminish dendritic cell and T cell responses driving immunotherapy resistance. This observation was corroborated in patient samples. CRISPR-Cas9-mediated gene targeting revealed that hyperactivation of the NRF2 antioxidant pathway is responsible for diminished immune responses in Keap1-mutant tumors. Importantly, we demonstrate that combining glutaminase inhibition with immune checkpoint blockade can reverse immunosuppression, making Keap1-mutant tumors susceptible to immunotherapy. Our study provides new insight into the role of KEAP1 mutations in immune evasion, paving the way for novel immune-based therapeutic strategies for KEAP1-mutant cancers.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 113295 |
| Tidsskrift | Cell Reports |
| Vol/bind | 42 |
| Udgave nummer | 11 |
| Sider (fra-til) | 1-25 |
| ISSN | 2211-1247 |
| DOI | |
| Status | Udgivet - 28 nov. 2023 |
Bibliografisk note
Funding Information:
T.P. has received research support from Agios Pharmaceuticals, and T.P. and S.B.K. have received funding from Dracen Pharmaceuticals, Kymera Therapeutics, and Bristol Myers Squibb. T.P. has received honoraria from Calithera Biosciences and Vividion Therapeutics. T.P. and S.B.K. are authors on US provisional patent application 16/483,835: “Methods for treating cancers having a deregulated NRF2/KEAP1 pathway.”
Funding Information:
Work in the T.P. laboratory was supported by NIH grants ( R37CA222504 and R01CA227649 ), an American Cancer Society Research Scholar grant ( RSG-17-200-01-TBE ), and the Emerald Foundation Young Investigator Award . Work in the S.B.K. laboratory was supported by NIH grants ( R01HL125816 and R01CA271245 ), a LEO Foundation grant ( LF-OC-20-000351 ), an NYU Cancer Center Pilot grant ( P30CA016087 ), and a Judith and Stewart Colton Center for Autoimmunity Pilot grant . W.L.W. is supported by NIH training grants ( T32GM007308 and 1F30CA247020 ). R.P. is supported by the William Rom Fellowship , the Stony Wold-Herbert Fund , and NIH T32 training grants ( T32CA009161 and T32AI100853 ). E.B. is supported by an NIH training grant ( T32AI100853-10 ). Work in the K.M.K. laboratory is supported by an NIH grant ( R01AI143861-01 ). A.T. is supported by NCI/NIH P01CA229086 and NCI/NIH R01CA252239 . T.B.B. was supported by the Danish Cancer Society (Kræftens Bekæmpelse). We would like to thank Drs. M. Okuniewska and S. Schwab (NYU) for providing OT-I mice and Dr. Thomas (NIH) for providing Ki696 and anti-NRF2 antibody. CB-839 was provided by Calithera. We thank the NYU Experimental Pathology Laboratory, Flow Cytometry Core, and Animal Resources Facility staff for their support and guidance. We thank the Genome Technology Center for expert library preparation and sequencing, and the Applied Bioinformatics Laboratories for providing bioinformatics support and helping with the analysis and interpretation of the data. These cores are partially supported by NYU Cancer Center grant P30CA016087. This work has used computing resources at the NYU School of Medicine High Performance Computing Facility. We are grateful to Drs. Frey and Reizis for their feedback on the manuscript.
Funding Information:
Work in the T.P. laboratory was supported by NIH grants (R37CA222504 and R01CA227649), an American Cancer Society Research Scholar grant (RSG-17-200-01-TBE), and the Emerald Foundation Young Investigator Award. Work in the S.B.K. laboratory was supported by NIH grants (R01HL125816 and R01CA271245), a LEO Foundation grant (LF-OC-20-000351), an NYU Cancer Center Pilot grant (P30CA016087), and a Judith and Stewart Colton Center for Autoimmunity Pilot grant. W.L.W. is supported by NIH training grants (T32GM007308 and 1F30CA247020). R.P. is supported by the William Rom Fellowship, the Stony Wold-Herbert Fund, and NIH T32 training grants (T32CA009161 and T32AI100853). E.B. is supported by an NIH training grant (T32AI100853-10). Work in the K.M.K. laboratory is supported by an NIH grant (R01AI143861-01). A.T. is supported by NCI/NIH P01CA229086 and NCI/NIH R01CA252239. T.B.B. was supported by the Danish Cancer Society (Kræftens Bekæmpelse). We would like to thank Drs. M. Okuniewska and S. Schwab (NYU) for providing OT-I mice and Dr. Thomas (NIH) for providing Ki696 and anti-NRF2 antibody. CB-839 was provided by Calithera. We thank the NYU Experimental Pathology Laboratory, Flow Cytometry Core, and Animal Resources Facility staff for their support and guidance. We thank the Genome Technology Center for expert library preparation and sequencing, and the Applied Bioinformatics Laboratories for providing bioinformatics support and helping with the analysis and interpretation of the data. These cores are partially supported by NYU Cancer Center grant P30CA016087. This work has used computing resources at the NYU School of Medicine High Performance Computing Facility. We are grateful to Drs. Frey and Reizis for their feedback on the manuscript. A.M.Z. led the project and conducted experiments with assistance from R.P. T.K. A.R. S.S. M.C. E.B. E.I. A.H. and S.R. Y.H. T.B.B. and A.M.Z. performed the bioinformatic analysis. W.L.W. generated the Keap1 vectors. A.K. provided advice and reagents for ICB experiments. R.P. and A.H.Y. performed the Nanostring analysis. H.I.P. provided human tumor samples, performed sequencing, and editing the manuscript. C.A.W. J.T.P. and C.M.R. provided the human tissue microarray. A.L.M. provided human samples and advice. K.M.K. supervised the mouse immunofluorescence experiments. A.T. supervised the bioinformatics analyses. K.K.W. provided conceptual advice. A.M.Z. drafted the manuscript. All authors reviewed and discussed the final version of the manuscript. T.P. has received research support from Agios Pharmaceuticals, and T.P. and S.B.K. have received funding from Dracen Pharmaceuticals, Kymera Therapeutics, and Bristol Myers Squibb. T.P. has received honoraria from Calithera Biosciences and Vividion Therapeutics. T.P. and S.B.K. are authors on US provisional patent application 16/483,835: “Methods for treating cancers having a deregulated NRF2/KEAP1 pathway.”
Publisher Copyright:
© 2023 The Author(s)
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