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Recurrent SERPINB3 and SERPINB4 mutations in patients who respond to anti-CTLA4 immunotherapy

Nature Genetics volume 48, pages 13271329 (2016) | Download Citation

Abstract

Immune checkpoint blockade has shown significant promise as an anticancer treatment, yet the determinants of response are not completely understood. Here we show that somatic mutations in SERPINB3 and SERPINB4 are associated with survival after anti-CTLA4 immunotherapy in two independent cohorts of patients with melanoma (n = 174). Interestingly, serpins are homologs of the well-known ovalbumin antigen and are associated with autoimmunity. Our findings have implications for the personalization of immunotherapy.

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Acknowledgements

We thank J. Wolchok, T. Merghoub, J. Yuan, P. Wong, and A. Snyder for collaborative interactions. We thank the Integrated Genomics Operation and the Ludwig Immune Monitoring Facility at Memorial Sloan Kettering for technical assistance. We thank A. Heguy and the Genome Technology Center at New York University and L. Mangarin for assistance with validation sequencing. This work was funded by a Pershing Square Sohn Cancer Research grant (T.A.C.), the Frederick Adler Chair (T.A.C.), Stand Up 2 Cancer (T.A.C.), the STARR Cancer Consortium (T.A.C.), and in part through NIH/NCI Cancer Center Support Grant P30 CA008748. Research supported by a Stand Up To Cancer – Cancer Research Institute Cancer Immunology Translational Cancer Research Grant. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research.

Author information

Author notes

    • Nadeem Riaz
    • , Jonathan J Havel
    •  & Sviatoslav M Kendall

    These authors contributed equally to this work.

Affiliations

  1. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Nadeem Riaz
    • , Jonathan J Havel
    • , Sviatoslav M Kendall
    • , Vladimir Makarov
    • , Logan A Walsh
    • , Alexis Desrichard
    •  & Timothy A Chan
  2. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Nadeem Riaz
    • , Nils Weinhold
    •  & Timothy A Chan
  3. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Nadeem Riaz
    •  & Timothy A Chan

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Contributions

T.A.C. and N.R. designed and conceived the study. Analysis of mutations in individual genes with outcome was performed by S.M.K., N.W., N.R., V.M., and J.J.H. Neoantigen analysis was performed by J.J.H., S.M.K., and V.M. Analysis of expression data was performed by L.A.W., A.D., and N.R. N.R., J.J.H., and T.A.C. prepared the manuscript. All authors participated in discussion of the final manuscript and interpretation of results.

Competing interests

T.A.C. is a co-founder of Gritstone Oncology.

Corresponding author

Correspondence to Timothy A Chan.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–3.

Excel files

  1. 1.

    Supplementary Table 1

    Recurrently mutated genes in melanoma as identified by InVex analysis performed by TCGA.

  2. 2.

    Supplementary Table 2

    Multivariate model of overall survival and SERPINB3 and SERPINB4 mutations.

  3. 3.

    Supplementary Table 3

    SERPINB3 and SERPINB4 mutations in both cohorts of patients.

  4. 4.

    Supplementary Table 4

    MHC class I predicted neoantigens from SERPINB3 and SERPINB4 mutations.

  5. 5.

    Supplementary Table 5

    MHC class II predicted neoantigens from SERPINB3 and SERPINB4 mutations.

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DOI

https://doi.org/10.1038/ng.3677

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