CD200 depletion in glioma enhances antitumor immunity and induces tumor rejection

Itay Raphael, Anzar A Mujeeb, Elisabet Ampudia-Mesias, ReidAnn E Sever, Brandon McClellan, Stephen C Frederico, Chaim T Sneiderman, Apoorva Mirji, Ali Daba, Francisco Puerta-Martinez, Michal Nisnboym, Wilson B Edwards, Michael Graner, Christopher Moertel, Maria G Castro, Gary Kohanbash, Michael Olin
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Abstract

High-grade gliomas are a major health challenge with poor prognosis and high morbidity. Immune-checkpoint inhibitors (ICI) have emerged as promising therapeutic options for several malignancies yet show little efficacy against central nervous system (CNS) tumors. CD200 is a newly recognized immune checkpoint that modulates immune homeostasis. CD200 protein is expressed by a variety of cells, including immune cells and stromal cells, and is overexpressed by many tumors. The shedding of CD200 from tumor cells can create an immunosuppressive environment that dampens anti-tumor immunity by modulating cytolytic activity and cytokine expression both within and outside the tumor microenvironment (TME). While it is well-accepted that CD200 induces a pro-tumorigenic environment through its ability to suppress the immune response, we sought to determine the role of glioma-specific expression of CD200. We show that CD200 is expressed across glioma types, is shed from tumor cells, and increases over time in the serum of patients undergoing immunotherapy. Using CD200 knockout (KO) glioma models, we demonstrated that glioma cell-derived CD200 promotes tumor growth in vivo and in vitro. Notably, CD200 KO gliomas are spontaneously rejected by their host, a process that required a fully functional immune system, including NK and T-cells. Moreover, we report that glioma-derived or brain-injected soluble CD200 contributes to the suppression of antigen-specific CD8 T-cells in the draining lymph nodes (dLNs). Our work provides new mechanistic insights regarding CD200-mediated immunosuppression by gliomas.
清除胶质瘤中的 CD200 可增强抗肿瘤免疫力并诱导肿瘤排斥反应
高级别胶质瘤是一项重大的健康挑战,预后差、发病率高。免疫检查点抑制剂(ICI)已成为治疗多种恶性肿瘤的理想选择,但对中枢神经系统(CNS)肿瘤的疗效甚微。CD200 是一种新发现的免疫检查点,可调节免疫稳态。CD200 蛋白由多种细胞表达,包括免疫细胞和基质细胞,并在许多肿瘤中过度表达。CD200 蛋白从肿瘤细胞脱落后,会形成一种免疫抑制环境,通过调节肿瘤微环境(TME)内外的细胞溶解活性和细胞因子表达,抑制抗肿瘤免疫。尽管 CD200 通过抑制免疫反应的能力诱导一种有利于肿瘤的环境已被广泛接受,但我们仍试图确定 CD200 在胶质瘤特异性表达中的作用。我们的研究表明,CD200在各种类型的胶质瘤中都有表达,会从肿瘤细胞中脱落,并在接受免疫治疗的患者血清中随着时间的推移而增加。通过使用 CD200 基因敲除(KO)胶质瘤模型,我们证明胶质瘤细胞衍生的 CD200 在体内和体外都能促进肿瘤生长。值得注意的是,CD200 KO胶质瘤会被宿主自发排斥,这一过程需要包括NK和T细胞在内的功能完善的免疫系统。此外,我们还报告了胶质瘤衍生或脑注射的可溶性 CD200 对引流淋巴结(dLNs)中抗原特异性 CD8 T 细胞的抑制作用。我们的研究为CD200介导的胶质瘤免疫抑制提供了新的机制认识。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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