2. Academic Validation
  3. PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment

PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment

  • J Immunother Cancer. 2022 Mar;10(3):e003402. doi: 10.1136/jitc-2021-003402.
Natalie B Collins 1 2,  Rose Al Abosy 1,  Brian C Miller 3,  Kevin Bi 4,  Qihong Zhao 5,  Michael Quigley 6,  Jeffrey J Ishizuka 7,  Kathleen B Yates 8 9,  Hans W Pope 10,  Robert T Manguso 8 9,  Yashaswi Shrestha 11,  Marc Wadsworth 8 12 13,  Travis Hughes 8 12 13,  Alex K Shalek 8 12 13,  Jesse S Boehm 8,  William C Hahn 4 8 14,  John G Doench 8,  W Nicholas Haining 15
Affiliations

Affiliations

  • 1 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 2 Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston Children's Hospital, Boston, Massachusetts, USA.
  • 3 Lineberger Comprehensive Cancer Center, Department of Medicine, Division of Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 5 Oncology Discovery Biology, Bristol Myers Squibb, Lawrenceville, New Jersey, USA.
  • 6 Research Biology, Gilead Sciences Inc, Foster City, California, USA.
  • 7 Department of Internal Medicine (Oncology), Yale Cancer Center and Yale School of Medicine, New Haven, New Jersey, USA.
  • 8 Broad Institute, Cambridge, Massachusetts, USA.
  • 9 Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
  • 10 Arsenal Biosciences, San Francisco, California, USA.
  • 11 AstraZeneca, Gaithersburg, Maryland, USA.
  • 12 Institute for Medical Engineering & Science (IMES), Department of Chemistry and Koch Institute for Integrative Cancer Research, Ragon Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
  • 13 Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.
  • 14 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • 15 Arsenal Biosciences, San Francisco, California, USA [email protected].
PMID: 35264433 DOI: 10.1136/jitc-2021-003402
Abstract

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.

Keywords

biomarkers; immune evation; immunotherapy; tumor.

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