Myeloid-derived suppressor cell subsets drive glioblastoma growth in a sex-specific manner

Defne Bayik; Yadi Zhou; Chihyun Park; Changjin Hong; Daniel Vail; Daniel J. Silver; Adam Lauko; Gustavo Roversi; Dionysios C. Watson; Alice Lo; Tyler J. Alban; Mary McGraw; Mia Sorensen; Matthew M. Grabowski; Balint Otvos; Michael A. Vogelbaum; Craig Horbinski; Bjarne Winther Kristensen; Ahmad M. Khalil; Tae Hyun Hwang; Manmeet S. Ahluwalia; Feixiong Cheng; Justin D. Lathia

doi:10.1158/2159-8290.CD-19-1355

Myeloid-derived suppressor cell subsets drive glioblastoma growth in a sex-specific manner

Defne Bayik, Yadi Zhou, Chihyun Park, Changjin Hong, Daniel Vail, Daniel J. Silver, Adam Lauko, Gustavo Roversi, Dionysios C. Watson, Alice Lo, Tyler J. Alban, Mary McGraw, Mia Sorensen, Matthew M. Grabowski, Balint Otvos, Michael A. Vogelbaum, Craig Horbinski, Bjarne Winther Kristensen, Ahmad M. Khalil, Tae Hyun HwangManmeet S. Ahluwalia, Feixiong Cheng, Justin D. Lathia^*

^*Corresponding author for this work

Pathology

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

156 Scopus citations

Abstract

Myeloid-derived suppressor cells (MDSC) that block antitumor immunity are elevated in glioblastoma (GBM) patient blood and tumors. However, the distinct con-tributions of monocytic (mMDSC) versus granulocytic (gMDSC) subsets have yet to be determined. In mouse models of GBM, we observed that mMDSCs were enriched in the male tumors, whereas gMDSCs were elevated in the blood of females. Depletion of gMDSCs extended survival only in female mice. Using gene-expression signatures coupled with network medicine analysis, we demonstrated in preclinical models that mMDSCs could be targeted with antiproliferative agents in males, whereas gMDSC function could be inhibited by IL1β blockade in females. Analysis of patient data confirmed that proliferating mMDSCs were predominant in male tumors and that a high gMDSC/IL1β gene signature correlated with poor prognosis in female patients. These findings demonstrate that MDSC subsets differentially drive immune suppression in a sex-specific manner and can be leveraged for therapeutic intervention in GBM. SIGNIFICANCE: Sexual dimorphism at the level of MDSC subset prevalence, localization, and gene-expression profile constitutes a therapeutic opportunity. Our results indicate that chemotherapy can be used to target mMDSCs in males, whereas IL1 pathway inhibitors can provide benefit to females via inhibition of gMDSCs.

Original language	English (US)
Pages (from-to)	1210-1225
Number of pages	16
Journal	Cancer discovery
Volume	10
Issue number	8
DOIs	https://doi.org/10.1158/2159-8290.CD-19-1355
State	Published - 2020

Funding

The authors thank the members of the Lathia Lab for insightful discussions. We would like to acknowledge technical help from Katy McCortney (Northwestern University), Emily Serbinowski and Lexie Trestan (Cleveland Clinic), the Cleveland Clinic Flow Cytometry Core, and Dr. John Peterson from the Cleveland Clinic Imaging Core. We greatly appreciate the editorial assistance of Dr. Erin Mulkearns-Hubert (Cleveland Clinic). We would like to thank Amanda Mendelsohn from the Center for Medical Art and Photography at the Cleveland Clinic for the illustrations. Recombinant IL2 was kindly provided by Dr. Marcela Diaz-Montero (Cleveland Clinic). This work was supported by the NIH grants R01NS109742 (to J.D. Lathia and M.A. Vogelbaum), F32 CA243314 (to D. Bayik), and R01NS102669 (to C. Horbinski), and by the Northwestern SPORE in Brain Cancer P50CA221747 (to C. Horbinski). This work was also supported by the Sontag Foundation (to J.D. Lathia), the American Brain Tumor Association (to J.D. Lathia), Case Comprehensive Cancer Center (to J.D. Lathia), Cleveland Clinic/Lerner Research Institute (to J.D. Lathia) and the Case Comprehensive Cancer Center Cancer Biology Training Award T32 CA059366 (to D. Bayik).

ASJC Scopus subject areas

Oncology

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Bayik, D., Zhou, Y., Park, C., Hong, C., Vail, D., Silver, D. J., Lauko, A., Roversi, G., Watson, D. C., Lo, A., Alban, T. J., McGraw, M., Sorensen, M., Grabowski, M. M., Otvos, B., Vogelbaum, M. A., Horbinski, C., Kristensen, B. W., Khalil, A. M., ... Lathia, J. D. (2020). Myeloid-derived suppressor cell subsets drive glioblastoma growth in a sex-specific manner. Cancer discovery, 10(8), 1210-1225. https://doi.org/10.1158/2159-8290.CD-19-1355

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title = "Myeloid-derived suppressor cell subsets drive glioblastoma growth in a sex-specific manner",

abstract = "Myeloid-derived suppressor cells (MDSC) that block antitumor immunity are elevated in glioblastoma (GBM) patient blood and tumors. However, the distinct con-tributions of monocytic (mMDSC) versus granulocytic (gMDSC) subsets have yet to be determined. In mouse models of GBM, we observed that mMDSCs were enriched in the male tumors, whereas gMDSCs were elevated in the blood of females. Depletion of gMDSCs extended survival only in female mice. Using gene-expression signatures coupled with network medicine analysis, we demonstrated in preclinical models that mMDSCs could be targeted with antiproliferative agents in males, whereas gMDSC function could be inhibited by IL1β blockade in females. Analysis of patient data confirmed that proliferating mMDSCs were predominant in male tumors and that a high gMDSC/IL1β gene signature correlated with poor prognosis in female patients. These findings demonstrate that MDSC subsets differentially drive immune suppression in a sex-specific manner and can be leveraged for therapeutic intervention in GBM. SIGNIFICANCE: Sexual dimorphism at the level of MDSC subset prevalence, localization, and gene-expression profile constitutes a therapeutic opportunity. Our results indicate that chemotherapy can be used to target mMDSCs in males, whereas IL1 pathway inhibitors can provide benefit to females via inhibition of gMDSCs.",

author = "Defne Bayik and Yadi Zhou and Chihyun Park and Changjin Hong and Daniel Vail and Silver, {Daniel J.} and Adam Lauko and Gustavo Roversi and Watson, {Dionysios C.} and Alice Lo and Alban, {Tyler J.} and Mary McGraw and Mia Sorensen and Grabowski, {Matthew M.} and Balint Otvos and Vogelbaum, {Michael A.} and Craig Horbinski and Kristensen, {Bjarne Winther} and Khalil, {Ahmad M.} and Hwang, {Tae Hyun} and Ahluwalia, {Manmeet S.} and Feixiong Cheng and Lathia, {Justin D.}",

note = "Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",

year = "2020",

doi = "10.1158/2159-8290.CD-19-1355",

language = "English (US)",

volume = "10",

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Bayik, D, Zhou, Y, Park, C, Hong, C, Vail, D, Silver, DJ, Lauko, A, Roversi, G, Watson, DC, Lo, A, Alban, TJ, McGraw, M, Sorensen, M, Grabowski, MM, Otvos, B, Vogelbaum, MA, Horbinski, C, Kristensen, BW, Khalil, AM, Hwang, TH, Ahluwalia, MS, Cheng, F & Lathia, JD 2020, 'Myeloid-derived suppressor cell subsets drive glioblastoma growth in a sex-specific manner', Cancer discovery, vol. 10, no. 8, pp. 1210-1225. https://doi.org/10.1158/2159-8290.CD-19-1355

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T1 - Myeloid-derived suppressor cell subsets drive glioblastoma growth in a sex-specific manner

AU - Bayik, Defne

AU - Zhou, Yadi

AU - Park, Chihyun

AU - Hong, Changjin

AU - Vail, Daniel

AU - Silver, Daniel J.

AU - Lauko, Adam

AU - Roversi, Gustavo

AU - Watson, Dionysios C.

AU - Lo, Alice

AU - Alban, Tyler J.

AU - McGraw, Mary

AU - Sorensen, Mia

AU - Grabowski, Matthew M.

AU - Otvos, Balint

AU - Vogelbaum, Michael A.

AU - Horbinski, Craig

AU - Kristensen, Bjarne Winther

AU - Khalil, Ahmad M.

AU - Hwang, Tae Hyun

AU - Ahluwalia, Manmeet S.

AU - Cheng, Feixiong

AU - Lathia, Justin D.

PY - 2020

Y1 - 2020

N2 - Myeloid-derived suppressor cells (MDSC) that block antitumor immunity are elevated in glioblastoma (GBM) patient blood and tumors. However, the distinct con-tributions of monocytic (mMDSC) versus granulocytic (gMDSC) subsets have yet to be determined. In mouse models of GBM, we observed that mMDSCs were enriched in the male tumors, whereas gMDSCs were elevated in the blood of females. Depletion of gMDSCs extended survival only in female mice. Using gene-expression signatures coupled with network medicine analysis, we demonstrated in preclinical models that mMDSCs could be targeted with antiproliferative agents in males, whereas gMDSC function could be inhibited by IL1β blockade in females. Analysis of patient data confirmed that proliferating mMDSCs were predominant in male tumors and that a high gMDSC/IL1β gene signature correlated with poor prognosis in female patients. These findings demonstrate that MDSC subsets differentially drive immune suppression in a sex-specific manner and can be leveraged for therapeutic intervention in GBM. SIGNIFICANCE: Sexual dimorphism at the level of MDSC subset prevalence, localization, and gene-expression profile constitutes a therapeutic opportunity. Our results indicate that chemotherapy can be used to target mMDSCs in males, whereas IL1 pathway inhibitors can provide benefit to females via inhibition of gMDSCs.

AB - Myeloid-derived suppressor cells (MDSC) that block antitumor immunity are elevated in glioblastoma (GBM) patient blood and tumors. However, the distinct con-tributions of monocytic (mMDSC) versus granulocytic (gMDSC) subsets have yet to be determined. In mouse models of GBM, we observed that mMDSCs were enriched in the male tumors, whereas gMDSCs were elevated in the blood of females. Depletion of gMDSCs extended survival only in female mice. Using gene-expression signatures coupled with network medicine analysis, we demonstrated in preclinical models that mMDSCs could be targeted with antiproliferative agents in males, whereas gMDSC function could be inhibited by IL1β blockade in females. Analysis of patient data confirmed that proliferating mMDSCs were predominant in male tumors and that a high gMDSC/IL1β gene signature correlated with poor prognosis in female patients. These findings demonstrate that MDSC subsets differentially drive immune suppression in a sex-specific manner and can be leveraged for therapeutic intervention in GBM. SIGNIFICANCE: Sexual dimorphism at the level of MDSC subset prevalence, localization, and gene-expression profile constitutes a therapeutic opportunity. Our results indicate that chemotherapy can be used to target mMDSCs in males, whereas IL1 pathway inhibitors can provide benefit to females via inhibition of gMDSCs.

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Myeloid-derived suppressor cell subsets drive glioblastoma growth in a sex-specific manner

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