DRES-13. VEGF BLOCKADE ENHANCES T REGULATORY CELL FUNCTION BY DYSREGULATING GLUTAMATE TRANSPORT IN GBM. (5th November 2018)

• Record Type: Journal Article
• Authors: Long, Yu; Karachi, Aida; Grippin, Adam; Tao, Haipeng; Zhang, Wang; Sayour, Elias; Deleyrolle, Loic; Mitchell, Duane; Lin, Zhiguo; Huang, Jianping
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi78
• Page End: vi78
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.320
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: In treating patients with cancer, inhibition of the VEGF pathway has been shown to prolong recurrence-free survival (RFS). However, anti-VEGF therapy has failed to improve overall survival in patients in randomized clinical trials. To help patients who are undergoing anti-angiogenic treatment, we attempted to tackle the obstacles of the treatment, using glioma animal models. In contrast to most literature reports focusing on the immediate post-treatment effect, we mainly investigated the animals that had failed the treatment. We found that tumor immunosuppression plays a critical role in treatment failure. Higher-doses of anti-VEGF treatment resulted in an over-representation of Tregs in tumor-infiltrating lymphocytes (TILs) and elevated expression of checkpoint molecules on TILs. The therapy mediates overexpression of xCT (a glutamate/cystine antiporter), which leads to excessive glutamate (a neurotoxin) production by glioma cells. The glutamate is responsible for the enhanced Treg suppressive function, which is signaling through upregulation of glutamate receptor 1(mGluR1) on the Tregs. Depleting CD25+ T cells prior to anti-VEGF therapy restores T cell production of IFN-g, enhancing the antitumor response. Collectively, VEGF blockade exacerbates Treg suppressive function by dysregulating glutamate antiport, and co-administration of Treg depletion with VEGF blockade can provide a synergetic antitumor effect for treating GBM.