Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma

Junfei Zhao; Andrew X. Chen; Robyn D. Gartrell; Andrew M. Silverman; Luis Aparicio; Tim Chu; Darius Bordbar; David Shan; Jorge Samanamud; Aayushi Mahajan; Ioan Filip; Rose Orenbuch; Morgan Goetz; Jonathan T. Yamaguchi; Michael Cloney; Craig Horbinski; Rimas V. Lukas; Jeffrey Raizer; Ali I. Rae; Jinzhou Yuan; Peter Canoll; Jeffrey N. Bruce; Yvonne M. Saenger; Peter Sims; Fabio M. Iwamoto; Adam M. Sonabend; Raul Rabadan

doi:10.1038/s41591-019-0349-y

Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma

Junfei Zhao, Andrew X. Chen, Robyn D. Gartrell, Andrew M. Silverman, Luis Aparicio, Tim Chu, Darius Bordbar, David Shan, Jorge Samanamud, Aayushi Mahajan, Ioan Filip, Rose Orenbuch, Morgan Goetz, Jonathan T. Yamaguchi, Michael Cloney, Craig Horbinski, Rimas V. Lukas, Jeffrey Raizer, Ali I. Rae, Jinzhou YuanPeter Canoll, Jeffrey N. Bruce, Yvonne M. Saenger, Peter Sims, Fabio M. Iwamoto, Adam M. Sonabend, Raul Rabadan

Research output: Contribution to journal › Article › peer-review

516 Scopus citations

Abstract

Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor’s clonal evolution during treatment.

Original language	English (US)
Pages (from-to)	462-469
Number of pages	8
Journal	Nature Medicine
Volume	25
Issue number	3
DOIs	https://doi.org/10.1038/s41591-019-0349-y
State	Published - Mar 1 2019
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Zhao, J., Chen, A. X., Gartrell, R. D., Silverman, A. M., Aparicio, L., Chu, T., Bordbar, D., Shan, D., Samanamud, J., Mahajan, A., Filip, I., Orenbuch, R., Goetz, M., Yamaguchi, J. T., Cloney, M., Horbinski, C., Lukas, R. V., Raizer, J., Rae, A. I., ... Rabadan, R. (2019). Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma. Nature Medicine, 25(3), 462-469. https://doi.org/10.1038/s41591-019-0349-y

Zhao, J, Chen, AX, Gartrell, RD, Silverman, AM, Aparicio, L, Chu, T, Bordbar, D, Shan, D, Samanamud, J, Mahajan, A, Filip, I, Orenbuch, R, Goetz, M, Yamaguchi, JT, Cloney, M, Horbinski, C, Lukas, RV, Raizer, J, Rae, AI, Yuan, J, Canoll, P, Bruce, JN, Saenger, YM, Sims, P, Iwamoto, FM, Sonabend, AM & Rabadan, R 2019, 'Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma', Nature Medicine, vol. 25, no. 3, pp. 462-469. https://doi.org/10.1038/s41591-019-0349-y

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abstract = "Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor{\textquoteright}s clonal evolution during treatment.",

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AU - Bruce, Jeffrey N.

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AU - Sims, Peter

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AU - Sonabend, Adam M.

AU - Rabadan, Raul

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Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma

Abstract

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