PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment
Background Oncogenes act in a cell-intrinsic way to promote tumorigenesis. Whether oncogenes also have a cell-extrinsic effect on suppressing the immune response to cancer is less well understood.Methods We use an in vivo expression screen of known cancer-associated somatic mutations in mouse syngen...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2022-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e003402.full |
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| author | Yashaswi Shrestha Michael Quigley Travis Hughes Robert T Manguso Natalie B Collins Rose Al Abosy Brian C Miller Kevin Bi Qihong Zhao Jeffrey J Ishizuka Kathleen B Yates Hans W Pope Marc Wadsworth Alex K Shalek Jesse S Boehm William C Hahn John G Doench W Nicholas Haining |
| author_facet | Yashaswi Shrestha Michael Quigley Travis Hughes Robert T Manguso Natalie B Collins Rose Al Abosy Brian C Miller Kevin Bi Qihong Zhao Jeffrey J Ishizuka Kathleen B Yates Hans W Pope Marc Wadsworth Alex K Shalek Jesse S Boehm William C Hahn John G Doench W Nicholas Haining |
| author_sort | Yashaswi Shrestha |
| collection | DOAJ |
| description | Background Oncogenes act in a cell-intrinsic way to promote tumorigenesis. Whether oncogenes also have a cell-extrinsic effect on suppressing the immune response to cancer is less well understood.Methods We use an in vivo expression screen of known cancer-associated somatic mutations in mouse syngeneic tumor models treated with checkpoint blockade to identify oncogenes that promote immune evasion. We then validated candidates from this screen in vivo and analyzed the tumor immune microenvironment of tumors expressing mutant protein to identify mechanisms of immune evasion.Results We found that expression of a catalytically active mutation in phospho-inositol 3 kinase (PI3K), PIK3CA c.3140A>G (H1047R) confers a selective growth advantage to tumors treated with immunotherapy that is reversed by pharmacological PI3K inhibition. PIK3CA H1047R-expression in tumors decreased the number of CD8+ T cells but increased the number of inhibitory myeloid cells following immunotherapy. Inhibition of myeloid infiltration by pharmacological or genetic modulation of Ccl2 in PIK3CA H1047R tumors restored sensitivity to programmed cell death protein 1 (PD-1) checkpoint blockade.Conclusions PI3K activation enables tumor immune evasion by promoting an inhibitory myeloid microenvironment. Activating mutations in PI3K may be useful as a biomarker of poor response to immunotherapy. Our data suggest that some oncogenes promote tumorigenesis by enabling tumor cells to avoid clearance by the immune system. Identification of those mechanisms can advance rational combination strategies to increase the efficacy of immunotherapy. |
| format | Article |
| id | doaj-art-2f18639e65804873a00ab93aef07c6bc |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-2f18639e65804873a00ab93aef07c6bc2025-08-20T02:16:44ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-003402PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironmentYashaswi Shrestha0Michael Quigley1Travis Hughes2Robert T Manguso3Natalie B Collins4Rose Al Abosy5Brian C Miller6Kevin Bi7Qihong Zhao8Jeffrey J Ishizuka9Kathleen B Yates10Hans W Pope11Marc Wadsworth12Alex K Shalek13Jesse S Boehm14William C Hahn15John G Doench16W Nicholas Haining17AstraZeneca, Gaithersburg, Maryland, USAPathology, Scripps Health, La Jolla, California, USABroad Institute, Cambridge, Massachusetts, USA3Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USADepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA1The University of North Carolina at Chapel Hill, Chapel Hill, NC, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USAOncology Discovery Biology, Bristol Myers Squibb, Lawrenceville, New Jersey, USADepartment of Internal Medicine (Oncology), Yale Cancer Center and Yale School of Medicine, New Haven, New Jersey, USA3Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USAArsenal Biosciences, San Francisco, California, USABroad Institute, Cambridge, Massachusetts, USAInstitute for Medical Engineering & Science (IMES), Department of Chemistry and Koch Institute for Integrative Cancer Research, Ragon Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USABroad Institute, Cambridge, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA2Broad Institute, Cambridge, MA, USAArsenal Biosciences, San Francisco, California, USABackground Oncogenes act in a cell-intrinsic way to promote tumorigenesis. Whether oncogenes also have a cell-extrinsic effect on suppressing the immune response to cancer is less well understood.Methods We use an in vivo expression screen of known cancer-associated somatic mutations in mouse syngeneic tumor models treated with checkpoint blockade to identify oncogenes that promote immune evasion. We then validated candidates from this screen in vivo and analyzed the tumor immune microenvironment of tumors expressing mutant protein to identify mechanisms of immune evasion.Results We found that expression of a catalytically active mutation in phospho-inositol 3 kinase (PI3K), PIK3CA c.3140A>G (H1047R) confers a selective growth advantage to tumors treated with immunotherapy that is reversed by pharmacological PI3K inhibition. PIK3CA H1047R-expression in tumors decreased the number of CD8+ T cells but increased the number of inhibitory myeloid cells following immunotherapy. Inhibition of myeloid infiltration by pharmacological or genetic modulation of Ccl2 in PIK3CA H1047R tumors restored sensitivity to programmed cell death protein 1 (PD-1) checkpoint blockade.Conclusions PI3K activation enables tumor immune evasion by promoting an inhibitory myeloid microenvironment. Activating mutations in PI3K may be useful as a biomarker of poor response to immunotherapy. Our data suggest that some oncogenes promote tumorigenesis by enabling tumor cells to avoid clearance by the immune system. Identification of those mechanisms can advance rational combination strategies to increase the efficacy of immunotherapy.https://jitc.bmj.com/content/10/3/e003402.full |
| spellingShingle | Yashaswi Shrestha Michael Quigley Travis Hughes Robert T Manguso Natalie B Collins Rose Al Abosy Brian C Miller Kevin Bi Qihong Zhao Jeffrey J Ishizuka Kathleen B Yates Hans W Pope Marc Wadsworth Alex K Shalek Jesse S Boehm William C Hahn John G Doench W Nicholas Haining PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment Journal for ImmunoTherapy of Cancer |
| title | PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment |
| title_full | PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment |
| title_fullStr | PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment |
| title_full_unstemmed | PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment |
| title_short | PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment |
| title_sort | pi3k activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment |
| url | https://jitc.bmj.com/content/10/3/e003402.full |
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