• A Corrigendum to this article was published on 14 December 2016

Abstract

Macrophages play critical, but opposite, roles in acute and chronic inflammation and cancer1,2,3,4,5. In response to pathogens or injury, inflammatory macrophages express cytokines that stimulate cytotoxic T cells, whereas macrophages in neoplastic and parasitic diseases express anti-inflammatory cytokines that induce immune suppression and may promote resistance to T cell checkpoint inhibitors1,2,3,4,5,6,7. Here we show that macrophage PI 3-kinase γ controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ signalling through Akt and mTor inhibits NFκB activation while stimulating C/EBPβ activation, thereby inducing a transcriptional program that promotes immune suppression during inflammation and tumour growth. By contrast, selective inactivation of macrophage PI3Kγ stimulates and prolongs NFκB activation and inhibits C/EBPβ activation, thus promoting an immunostimulatory transcriptional program that restores CD8+ T cell activation and cytotoxicity. PI3Kγ synergizes with checkpoint inhibitor therapy to promote tumour regression and increased survival in mouse models of cancer. In addition, PI3Kγ-directed, anti-inflammatory gene expression can predict survival probability in cancer patients. Our work thus demonstrates that therapeutic targeting of intracellular signalling pathways that regulate the switch between macrophage polarization states can control immune suppression in cancer and other disorders.

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Acknowledgements

This work was supported by NIH grants R01CA126820 (J.A.V.), T32HL098062 (M.M.K.), T32CA009523 (S.G.) and T32CA121938 (S.G.), the CAPES Foundation and Ministry of Education of Brazil (C.F.) and by Ralph and Fernanda Whitworth and the Immunotherapy Foundation (J.A.V. and E.E.C.). The authors thank J. Lee and S. Schoenberger for HPV+MEER HNSCC and SSCVII cells.

Author information

Affiliations

  1. Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA

    • Megan M. Kaneda
    • , Karen S. Messer
    • , Natacha Ralainirina
    • , Hongying Li
    • , Christopher J. Leem
    • , Sara Gorjestani
    • , Gyunghwi Woo
    • , Abraham V. Nguyen
    • , Camila C. Figueiredo
    • , Philippe Foubert
    • , Michael C. Schmid
    • , Ezra E. W. Cohen
    •  & Judith A. Varner
  2. Division of Biostatistics and Bioinformatics; Department of Family Medicine and Public Health University of California, San Diego, La Jolla, California 92093, USA

    • Karen S. Messer
    •  & Hongying Li
  3. Dep. Biologia Celular, UERJ, Rio de Janeiro, 20550-013, Brazil

    • Camila C. Figueiredo
  4. Infinity Pharmaceuticals, Cambridge, Massachusetts 02139, USA

    • Melissa Pink
    • , David G. Winkler
    • , Matthew Rausch
    • , Vito J. Palombella
    • , Jeffery Kutok
    •  & Karen McGovern
  5. Department of Pediatrics, University of California, San Diego, La Jolla, California 92093, USA

    • Kelly A. Frazer
  6. Institute for Genomic Medicine, University of California, San Diego, La Jolla, California 92093, USA

    • Kelly A. Frazer
  7. Department of Pharmacology, University of California, San Diego, La Jolla, California 92093, USA

    • Xuefeng Wu
    •  & Michael Karin
  8. Center for Computational Biology and Bioinformatics, Institute for Genomic Medicine, University of California, San Diego, La Jolla, California 92093, USA

    • Roman Sasik
  9. Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA

    • Ezra E. W. Cohen
    •  & Judith A. Varner
  10. Department of Pathology, University of California, San Diego, La Jolla, California 92093, USA

    • Judith A. Varner

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Contributions

TCGA analysis was performed by H.L. and K.S.M., RNA sequencing by K.A.F., M.M.K., S.G. and R.S., flow cytometry by M.M.K. and N.R., in vitro studies by M.M.K., N.R., S.G., G.W., C.C.F., A.V.N. and M.C.S., and animal studies by M.M.K., N.R., C.L. and P.F. M.P., V.J.P., J.K., K.M., M.R. and D.G.W. provided IPI-549 and carried out experiments for Fig.1c, Extended Data Fig. 8a–b. ML120B was contributed by X.W. and M.K. The project was directed by E.E.W.C., K.S.M. and J.A.V. The manuscript was written by J.A.V. and M.M.K.

Competing interests

M.P., V.J.P., J.K., K.M., M.R. and D.G.W. are former employees of Infinity Pharmaceuticals and J.A.V. received research support from Infinity Pharmaceuticals.

Corresponding author

Correspondence to Judith A. Varner.

Reviewer Information Nature thanks F. Balkwill, M. de Palma and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data

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    Supplementary Data

    This file contains source data for all gels used in Figure 2 and Extended Data Figures 1 and 6.

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DOI

https://doi.org/10.1038/nature19834

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