Recent clinical trials using immunotherapy have demonstrated its potential to control cancer by disinhibiting the immune system. Immune checkpoint blocking (ICB) antibodies against cytotoxic-T-lymphocyte-associated protein 4 or programmed cell death protein 1/programmed death-ligand 1 have displayed durable clinical responses in various cancers1. Although these new immunotherapies have had a notable effect on cancer treatment, multiple mechanisms of immune resistance exist in tumours. Among the key mechanisms, myeloid cells have a major role in limiting effective tumour immunity2,3,4. Growing evidence suggests that high infiltration of immune-suppressive myeloid cells correlates with poor prognosis and ICB resistance5,6. These observations suggest a need for a precision medicine approach in which the design of the immunotherapeutic combination is modified on the basis of the tumour immune landscape to overcome such resistance mechanisms. Here we employ a pre-clinical mouse model system and show that resistance to ICB is directly mediated by the suppressive activity of infiltrating myeloid cells in various tumours. Furthermore, selective pharmacologic targeting of the gamma isoform of phosphoinositide 3-kinase (PI3Kγ), highly expressed in myeloid cells, restores sensitivity to ICB. We demonstrate that targeting PI3Kγ with a selective inhibitor, currently being evaluated in a phase 1 clinical trial (NCT02637531), can reshape the tumour immune microenvironment and promote cytotoxic-T-cell-mediated tumour regression without targeting cancer cells directly. Our results introduce opportunities for new combination strategies using a selective small molecule PI3Kγ inhibitor, such as IPI-549, to overcome resistance to ICB in patients with high levels of suppressive myeloid cell infiltration in tumours.

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We would like to thank the Flow Cytometry and Integrated Genomics Operation Core Facilities at MSKCC. Swim Across America, Ludwig Institute for Cancer Research, Parker Institute for Cancer Immunotherapy, Center for Experimental Therapeutics at MSKCC (ETC), and the Breast Cancer Research Foundation supported this work. The work was also supported in part by the MSKCC Core Grant (P30 CA008748). O.D.H. was supported by J. Houtard foundation, Nuovo Soldati Foundation and Wallonie-Bruxelles International. We would also like to thank Y. Senbabaoglu for his help in bioinformatics data analysis, A. Bossert for his contribution as part of the GME program as well as J. Gladstone and K. Walsh for their contributions while working as co-op students in the laboratory.

Author information

Author notes

    • Jedd D. Wolchok
    •  & Taha Merghoub

    These authors jointly supervised this work.


  1. Memorial Sloan Kettering Cancer Center, Parker Institute for Cancer Immunotherapy and Swim Across America/Ludwig Collaborative Laboratory, New York, New York 10065, USA

    • Olivier De Henau
    • , Luis Felipe Campesato
    • , Cailian Liu
    • , Daniel Hirschhorn Cymerman
    • , Sadna Budhu
    • , Arnab Ghosh
    • , Jedd D. Wolchok
    •  & Taha Merghoub
  2. Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA

    • Matthew Rausch
    • , David Winkler
    • , Melissa Pink
    • , Jeremy Tchaicha
    • , Mark Douglas
    • , Thomas Tibbitts
    • , Sujata Sharma
    • , Jennifer Proctor
    • , Nicole Kosmider
    • , Kerry White
    • , Howard Stern
    • , John Soglia
    • , Julian Adams
    • , Vito J. Palombella
    • , Karen McGovern
    •  & Jeffery L. Kutok
  3. Weill Cornell Medical and Graduate Schools, New York, New York 10065, USA

    • Jedd D. Wolchok


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O.D.H., T.M., J.D.W., K.M., J.L.K, V.J.P. and J.A. developed the concepts and discussed experiments. O.D.H., T.M., J.D.W., K.M. and J.L.K. wrote the manuscript. O.D.H., M.R., D.W., L.F.C., D.H.C., S.B., A.G., M.P., J.P. and N.K. performed and analysed animal model experiments, flow cytometry experiments and functional assays. C.L. provided technical assistance; S.S. and K.W. performed assays in human samples. M.D., T.T. and H.S. performed transcriptomic analysis. J.T. and J.S. performed pharmacodynamics and pharmacokinetics studies.

Competing interests

All authors with affiliation to Infinity Pharmaceuticals, Inc. were employees and shareholders at Infinity Pharmaceuticals, Inc. at the time of the study. All other authors have no competing interests.

Corresponding authors

Correspondence to Jedd D. Wolchok or Taha Merghoub.

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.

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