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 Michael Horbinski, Rimas Vincas Lukas, Jeffrey Raizer, Ali I. Rae, Jinzhou Yuan & 7 others Peter Canoll, Jeffrey N. Bruce, Yvonne M. Saenger, Peter Sims, Fabio M. Iwamoto, Adam Mendel Sonabend Worthalter, Raul Rabadan

Research output: Contribution to journalLetter

6 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)462-469
Number of pages8
JournalNature Medicine
Volume25
Issue number3
DOIs
StatePublished - Mar 1 2019

Fingerprint

Glioblastoma
Immunotherapy
Tumors
Clonal Evolution
Neoplasms
Tumor Microenvironment
Immunosuppressive Agents
T-cells
Therapeutics
Infiltration
T-Lymphocytes
Mutation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Zhao, J., Chen, A. X., Gartrell, R. D., Silverman, A. M., Aparicio, L., Chu, T., ... 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, Junfei ; Chen, Andrew X. ; Gartrell, Robyn D. ; Silverman, Andrew M. ; Aparicio, Luis ; Chu, Tim ; Bordbar, Darius ; Shan, David ; Samanamud, Jorge ; Mahajan, Aayushi ; Filip, Ioan ; Orenbuch, Rose ; Goetz, Morgan ; Yamaguchi, Jonathan T. ; Cloney, Michael ; Horbinski, Craig Michael ; Lukas, Rimas Vincas ; Raizer, Jeffrey ; Rae, Ali I. ; Yuan, Jinzhou ; Canoll, Peter ; Bruce, Jeffrey N. ; Saenger, Yvonne M. ; Sims, Peter ; Iwamoto, Fabio M. ; Sonabend Worthalter, Adam Mendel ; Rabadan, Raul. / Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma. In: Nature Medicine. 2019 ; Vol. 25, No. 3. pp. 462-469.
@article{44962c91836e492f8d0a412e875e125b,
title = "Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma",
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.",
author = "Junfei Zhao and Chen, {Andrew X.} and Gartrell, {Robyn D.} and Silverman, {Andrew M.} and Luis Aparicio and Tim Chu and Darius Bordbar and David Shan and Jorge Samanamud and Aayushi Mahajan and Ioan Filip and Rose Orenbuch and Morgan Goetz and Yamaguchi, {Jonathan T.} and Michael Cloney and Horbinski, {Craig Michael} and Lukas, {Rimas Vincas} and Jeffrey Raizer and Rae, {Ali I.} and Jinzhou Yuan and Peter Canoll and Bruce, {Jeffrey N.} and Saenger, {Yvonne M.} and Peter Sims and Iwamoto, {Fabio M.} and {Sonabend Worthalter}, {Adam Mendel} and Raul Rabadan",
year = "2019",
month = "3",
day = "1",
doi = "10.1038/s41591-019-0349-y",
language = "English (US)",
volume = "25",
pages = "462--469",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "3",

}

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, CM, Lukas, RV, Raizer, J, Rae, AI, Yuan, J, Canoll, P, Bruce, JN, Saenger, YM, Sims, P, Iwamoto, FM, Sonabend Worthalter, 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

Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma. / Zhao, Junfei; Chen, Andrew X.; Gartrell, Robyn D.; Silverman, Andrew M.; Aparicio, Luis; Chu, Tim; Bordbar, Darius; Shan, David; Samanamud, Jorge; Mahajan, Aayushi; Filip, Ioan; Orenbuch, Rose; Goetz, Morgan; Yamaguchi, Jonathan T.; Cloney, Michael; Horbinski, Craig Michael; Lukas, Rimas Vincas; Raizer, Jeffrey; Rae, Ali I.; Yuan, Jinzhou; Canoll, Peter; Bruce, Jeffrey N.; Saenger, Yvonne M.; Sims, Peter; Iwamoto, Fabio M.; Sonabend Worthalter, Adam Mendel; Rabadan, Raul.

In: Nature Medicine, Vol. 25, No. 3, 01.03.2019, p. 462-469.

Research output: Contribution to journalLetter

TY - JOUR

T1 - Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma

AU - Zhao, Junfei

AU - Chen, Andrew X.

AU - Gartrell, Robyn D.

AU - Silverman, Andrew M.

AU - Aparicio, Luis

AU - Chu, Tim

AU - Bordbar, Darius

AU - Shan, David

AU - Samanamud, Jorge

AU - Mahajan, Aayushi

AU - Filip, Ioan

AU - Orenbuch, Rose

AU - Goetz, Morgan

AU - Yamaguchi, Jonathan T.

AU - Cloney, Michael

AU - Horbinski, Craig Michael

AU - Lukas, Rimas Vincas

AU - Raizer, Jeffrey

AU - Rae, Ali I.

AU - Yuan, Jinzhou

AU - Canoll, Peter

AU - Bruce, Jeffrey N.

AU - Saenger, Yvonne M.

AU - Sims, Peter

AU - Iwamoto, Fabio M.

AU - Sonabend Worthalter, Adam Mendel

AU - Rabadan, Raul

PY - 2019/3/1

Y1 - 2019/3/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85061351834&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061351834&partnerID=8YFLogxK

U2 - 10.1038/s41591-019-0349-y

DO - 10.1038/s41591-019-0349-y

M3 - Letter

VL - 25

SP - 462

EP - 469

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 3

ER -

Zhao J, Chen AX, Gartrell RD, Silverman AM, Aparicio L, Chu T et al. Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma. Nature Medicine. 2019 Mar 1;25(3):462-469. https://doi.org/10.1038/s41591-019-0349-y