By screening PD-1-sensitive tumors expressing recurrent human cancer-associated somatic mutations in syngeneic mice, Collins et al. showed that expression of a catalytically active PI3K mutant promoted tumor growth in anti-PD-1-treated WT mice. The PI3K mutant TME had fewer CD8+ T cells, more inhibitory CCR2hi myeloid cells, and was less inflamed than the control TME after anti-PD-1 treatment. Anti-PD-1 response of mice was restored by reducing myeloid cells in tumors with PI3K or CCR2/5 inhibitors, or by Ccl2 deletion from tumors. In human cancers, a positive correlation was observed for PI3K mutations, CCR2 expression, and M2 macrophage infiltration.
Contributed by Paula Hochman
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.
Author Info: (1) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston Children's H
Author Info: (1) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston Children's Hospital, Boston, Massachusetts, USA. (2) Department of Pediatric Oncology, Dana-Farber Cancer Institute, 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. Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA. (9) Arsenal Biosciences, San Francisco, California, USA. (10) Broad Institute, Cambridge, Massachusetts, USA. Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA. (11) AstraZeneca, Gaithersburg, Maryland, USA. (12) Broad Institute, Cambridge, Massachusetts, USA. 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. Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA. (13) Broad Institute, Cambridge, Massachusetts, USA. 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. Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA. (14) Broad Institute, Cambridge, Massachusetts, USA. 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. Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA. (15) Broad Institute, Cambridge, Massachusetts, USA. (16) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Broad Institute, Cambridge, Massachusetts, USA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. (17) Broad Institute, Cambridge, Massachusetts, USA. (18) Arsenal Biosciences, San Francisco, California, USA nhaining@arsenalbio.com.
