Regulation of tumor immune suppression and cancer cell survival by CXCL1/2 elevation in glioblastoma multiforme

Jiemiao Hu; Qingnan Zhao; Ling Yuan Kong; Jian Wang; Jun Yan; Xueqing Xia; Zhiliang Jia; Amy B. Heimberger; Shulin Li

doi:10.1126/sciadv.abc2511

Regulation of tumor immune suppression and cancer cell survival by CXCL1/2 elevation in glioblastoma multiforme

Jiemiao Hu, Qingnan Zhao, Ling Yuan Kong, Jian Wang, Jun Yan, Xueqing Xia, Zhiliang Jia, Amy B. Heimberger^*, Shulin Li^*

^*Corresponding author for this work

Neurological Surgery

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

57 Scopus citations

Abstract

The invasiveness and high immune suppression of glioblastoma multiforme (GBM) produce poor survival of afflicted patients. Unfortunately, in the past decades, no therapeutic approach has remarkably improved the survival time of patients with GBM. Our analysis of the TCGA database and brain tumor tissue arrays indicated that CXCL1 and CXCL2 overexpression is closely associated with GBM's aggressiveness. Our results showed that elevation of CXCL1 or CXCL2 facilitated myeloid cell migration and simultaneously disrupted CD8⁺T cell accumulation at tumor sites, causing accelerated tumor progression. Yet, blockade of CXCL1/2 significantly prevented myeloid-derived suppressor cell migration and thereby increased CD8⁺T cell accumulation in vitro and in vivo. CXCL1/2 also promoted the paracrine factor S100A9 and further activated Erk1/2 and p70S60k, whereas blocking CXCL1/2 down-regulated these prosurvival factors. The combination of targeting CXCL1/2 and standard temozolomide chemotherapy improved upon the antitumor efficacy of chemotherapy alone, extending the overall survival time in GBM.

Original language	English (US)
Article number	eabc2511
Journal	Science Advances
Volume	7
Issue number	5
DOIs	https://doi.org/10.1126/sciadv.abc2511
State	Published - Jan 27 2021

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title = "Regulation of tumor immune suppression and cancer cell survival by CXCL1/2 elevation in glioblastoma multiforme",

abstract = "The invasiveness and high immune suppression of glioblastoma multiforme (GBM) produce poor survival of afflicted patients. Unfortunately, in the past decades, no therapeutic approach has remarkably improved the survival time of patients with GBM. Our analysis of the TCGA database and brain tumor tissue arrays indicated that CXCL1 and CXCL2 overexpression is closely associated with GBM's aggressiveness. Our results showed that elevation of CXCL1 or CXCL2 facilitated myeloid cell migration and simultaneously disrupted CD8+T cell accumulation at tumor sites, causing accelerated tumor progression. Yet, blockade of CXCL1/2 significantly prevented myeloid-derived suppressor cell migration and thereby increased CD8+T cell accumulation in vitro and in vivo. CXCL1/2 also promoted the paracrine factor S100A9 and further activated Erk1/2 and p70S60k, whereas blocking CXCL1/2 down-regulated these prosurvival factors. The combination of targeting CXCL1/2 and standard temozolomide chemotherapy improved upon the antitumor efficacy of chemotherapy alone, extending the overall survival time in GBM.",

author = "Jiemiao Hu and Qingnan Zhao and Kong, {Ling Yuan} and Jian Wang and Jun Yan and Xueqing Xia and Zhiliang Jia and Heimberger, {Amy B.} and Shulin Li",

note = "Funding Information: This research was supported by grants from the U.S. NIH (CA203493) to S.L. This study was also supported by the Cancer Center Support Grant P30 CA016672. The following MD Anderson Cancer Center Support Grant core resources were used: Genetically Engineered Mouse Facility and Veterinary Pathology Services. Publisher Copyright: {\textcopyright} 2021 American Association for the Advancement of Science. All rights reserved.",

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AU - Hu, Jiemiao

AU - Zhao, Qingnan

AU - Kong, Ling Yuan

AU - Wang, Jian

AU - Yan, Jun

AU - Xia, Xueqing

AU - Jia, Zhiliang

AU - Heimberger, Amy B.

AU - Li, Shulin

N1 - Funding Information: This research was supported by grants from the U.S. NIH (CA203493) to S.L. This study was also supported by the Cancer Center Support Grant P30 CA016672. The following MD Anderson Cancer Center Support Grant core resources were used: Genetically Engineered Mouse Facility and Veterinary Pathology Services. Publisher Copyright: © 2021 American Association for the Advancement of Science. All rights reserved.

PY - 2021/1/27

Y1 - 2021/1/27

N2 - The invasiveness and high immune suppression of glioblastoma multiforme (GBM) produce poor survival of afflicted patients. Unfortunately, in the past decades, no therapeutic approach has remarkably improved the survival time of patients with GBM. Our analysis of the TCGA database and brain tumor tissue arrays indicated that CXCL1 and CXCL2 overexpression is closely associated with GBM's aggressiveness. Our results showed that elevation of CXCL1 or CXCL2 facilitated myeloid cell migration and simultaneously disrupted CD8+T cell accumulation at tumor sites, causing accelerated tumor progression. Yet, blockade of CXCL1/2 significantly prevented myeloid-derived suppressor cell migration and thereby increased CD8+T cell accumulation in vitro and in vivo. CXCL1/2 also promoted the paracrine factor S100A9 and further activated Erk1/2 and p70S60k, whereas blocking CXCL1/2 down-regulated these prosurvival factors. The combination of targeting CXCL1/2 and standard temozolomide chemotherapy improved upon the antitumor efficacy of chemotherapy alone, extending the overall survival time in GBM.

AB - The invasiveness and high immune suppression of glioblastoma multiforme (GBM) produce poor survival of afflicted patients. Unfortunately, in the past decades, no therapeutic approach has remarkably improved the survival time of patients with GBM. Our analysis of the TCGA database and brain tumor tissue arrays indicated that CXCL1 and CXCL2 overexpression is closely associated with GBM's aggressiveness. Our results showed that elevation of CXCL1 or CXCL2 facilitated myeloid cell migration and simultaneously disrupted CD8+T cell accumulation at tumor sites, causing accelerated tumor progression. Yet, blockade of CXCL1/2 significantly prevented myeloid-derived suppressor cell migration and thereby increased CD8+T cell accumulation in vitro and in vivo. CXCL1/2 also promoted the paracrine factor S100A9 and further activated Erk1/2 and p70S60k, whereas blocking CXCL1/2 down-regulated these prosurvival factors. The combination of targeting CXCL1/2 and standard temozolomide chemotherapy improved upon the antitumor efficacy of chemotherapy alone, extending the overall survival time in GBM.

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Regulation of tumor immune suppression and cancer cell survival by CXCL1/2 elevation in glioblastoma multiforme

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