An Immunogenic Model of KRAS-Mutant Lung Cancer Enables Evaluation of Targeted Therapy and Immunotherapy Combinations

Jesse Boumelha, Sophie de Carné Trécesson, Emily K. Law, Pablo Romero-Clavijo, Matthew A. Coelho, Kevin W. Ng, Edurne Mugarza, Christopher Moore, Sareena Rana, Deborah R. Caswell, Miguel Murillo, David C. Hancock, Prokopios Argyris, William L. Brown, Cameron C Durfee, Lindsay K Larson, Rachel I Vogel, Alejandro Suárez-Bonnet, Simon L. Priestnall, Philip EastSarah J. Ross, George Kassiotis, Miriam Molina-Arcas, Charles Swanton, Reuben Harris, Julian Downward

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Mutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins cause tumor regression but ultimately fail to elicit cures. As a result, there is an intense interest in how to best combine targeted therapies with other treatments, such as immunotherapies. However, preclinical systems for studying the interaction of lung tumors with the host immune system are inadequate, in part due to the low tumor mutational burden in genetically engineered mouse models. Here we set out to develop mouse models of mutant KRAS–driven lung cancer with an elevated tumor mutational burden by expressing the human DNA cytosine deaminase, APOBEC3B, to mimic the mutational signature seen in human lung cancer. This failed to substantially increase clonal tumor mutational burden and autochthonous tumors remained refractory to immunotherapy. However, establishing clonal cell lines from these tumors enabled the generation of an immunogenic syngeneic transplantation model of KRAS-mutant lung adenocarcinoma that was sensitive to immunotherapy. Unexpectedly, antitumor immune responses were not directed against neoantigens but instead targeted derepressed endogenous retroviral antigens. The ability of KRASG12C inhibitors to cause regression of KRASG12C -expressing tumors was markedly potentiated by the adaptive immune system, highlighting the importance of using immunocompetent models for evaluating targeted therapies. Overall, this model provides a unique opportunity for the study of combinations of targeted and immunotherapies in immune-hot lung cancer.

Original languageEnglish (US)
Pages (from-to)3435-3448
Number of pages14
JournalCancer Research
Volume82
Issue number19
DOIs
StatePublished - Oct 1 2022

Bibliographical note

Funding Information:
S. de CarnéTrécesson reports personal fees from Revolution Medicines, Inc. outside the submitted work. R.I. Vogel reports grants from NIH during the conduct of the study. S.J. Ross reports personal fees and other support from AstraZeneca outside the submitted work, and S.J. Ross is an employee and shareholder of AstraZeneca. G. Kassiotis reports personal fees from EnaraBio outside the submitted work and that he is a scientific co-founder and advisory board member of EnaraBio. C. Swanton reports grants, personal fees, and other support from AstraZeneca, grants from Boehringer-Ingelheim, grants and personal fees from Bristol Myers Squibb, grants from Pfizer, grants and personal fees from Roche-Ventana, grants from Invitae, grants from Ono Pharmaceutical, personal fees and other support from Achilles Therapeutics, personal fees and other support from GRAIL, other support from Epic Biosciences, other support from Apogen Biotechnologies, personal fees and other support from Bicycle Therapeutics, personal fees from Amgen, personal fees from Novartis, personal fees from GlaxoSmithKline, personal fees from MSD, personal fees from Illumina, personal fees from Genentech, personal fees from Medicxi, personal fees from Metabomed, personal fees from Roche Innovation Centre Shanghai, and personal fees from Sarah Canon Research Institute during the conduct of the study; grants, personal fees, and other support from AstraZeneca, grants from Beohringer Ingel-heim, grants and personal fees from Bristol Myers Squibb, grants from Pfizer, grants and personal fees from Roche Ventana, grants from Invitae, grants from Ono Pharmaceutical, personal fees and other support from Achilles Therapeutics, personal fees and other support from GRAIL, other support from Epic Bioscience, other support from Apogen Biotechnologies, personal fees and other support from Bicycle Therapeutics, personal fees from Amgen, personal fees from Novartis, personal fees from GSK, personal fees from MSD, personal fees from Illumina, personal fees from Genentech, personal fees from Medicxi, personal fees from Metabomed, personal fees from Roche Innovation Centre Shanghai, and personal fees from Sarah Canon Research Institute outside the submitted work; in addition, C. Swanton has a patent for PCT/GB2017/053289 issued, a patent for to targeting neoantigens (PCT/EP2016/ 059401) issued, a patent for identifying patent response to immune checkpoint blockade (PCT/EP2016/071471) issued, a patent for determining HLA LOH (PCT/ GB2018/052004) issued, a patent for predicting survival rates of patients with cancer (PCT/GB2020/050221) issued, a patent for identifying patients who respond to cancer treatment (PCT/GB2018/051912) issued, a US patent relating to detecting tumor mutations (PCT/US2017/28013) issued, a patent for methods for lung cancer detection (US20190106751A1) issued, and S. de CarnéTrécesson has a patent for European and US patent related to identifying insertion/deletion mutation targets (PCT/GB2018/051892 issued; and C. Swanton is a Royal Society Napier Research Professor (RSRP\R\210001). This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001169), the UK Medical Research Council (FC001169), and the Wellcome Trust (FC001169). This research was funded in whole, or in part, by the Wellcome Trust (FC001169). For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. C. Swanton is funded by Cancer Research UK (TRACERx (C11496/A17786), PEACE (C416/ A21999) and CRUK Cancer Immunotherapy Catalyst Network); Cancer Research UK Lung Cancer Centre of Excellence (C11496/A30025); the Rosetrees Trust, Butterfield and Stoneygate Trusts; NovoNordisk Foundation (ID16584); Royal Society Professorship Enhancement Award (RP/EA/180007); National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre; the Cancer Research UK-University College London Centre; Experimental Cancer Medicine Centre; the Breast Cancer Research Foundation (US); and The Mark Foundation for Cancer Research (Grant 21-029-ASP). This work was supported by a Stand Up To Cancer-LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (Grant Number: SU2C-AACR-DT23-17 to S.M. Dubinett and A.E. Spira). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C. Swanton is in receipt of an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 835297). J. Downward reports grants from European Research Council and grants from Wellcome Trust during the conduct of the study; personal fees from Vividion, personal fees from BridgeBio, personal fees from Theras, grants and personal fees from AstraZeneca, grants from Bristol Myers Squibb, and grants from Revolution Medicines outside the submitted work. No disclosures were reported by the other authors.

Funding Information:
The authors thank the science technology platforms at the Francis Crick Institute including Biological Resources, Scientific Computing, Bioinformatics and Biostatistics, Flow Cytometry, Experimental Histopathology, and Cell Services. They also thank Colleen Forster and Gerard O’Sullivan for assistance with IHC and pathology, Yasuhiko Kawakami for sharing CMV-Cre animals, and Brian Dunnette for expertise with the Aperio ScanScope XT at the University of Minnesota. This work was supported by funding to J.D. from the Francis Crick Institute—which receives its core funding from Cancer Research UK (FC001070), the UK Medical Research Council (FC001070), and the Wellcome Trust (FC001070)—from the European Research Council Advanced Grant RASImmune, and from a Wellcome Trust Senior Investigator Award 103799/Z/14/Z. The A3Bi minigene model was developed with support from the National Cancer Institute P01-CA234228 (R. Harris), Team Judy (R. Harris), Randy Shaver Cancer Research and Community Fund (R. Harris), University of Minnesota Masonic Cancer Center, and College of Biological Sciences (R. Harris). R. Harris is the Ewing Halsell President’s Council Distinguished Chair at University of Texas San Antonio and an Investigator of the Howard Hughes Medical Institute. S. de Carné Trécesson received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 703228.

Publisher Copyright:
©2022 American Association for Cancer Research.

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