Chitinase-3-like-1 mediated immunosuppression in Glioblastoma

项目摘要 胶质母细胞瘤(GBM)是最常见和致命的脑肿瘤，中位生存期约15个月。 尽管进行了密集的多模式治疗，包括免疫治疗。GBM具有高度的免疫抑制作用， 免疫治疗耐药是因为胶质瘤细胞通过改变 肿瘤微环境。由于肿瘤细胞和周围TME的多样性和可塑性， 对GBM逃避免疫的机制的了解仍然难以捉摸。我们的长期目标是解剖 肿瘤细胞的内在机制，它重新编程GBM的TME，以开发有效的治疗方法。 我们最近发现几丁质酶-3-样-1(CHI3L1)是一种在基底膜中高表达和分泌的糖蛋白，是一种 调解免疫逃避的候选人。我们的中心发现是沉默同基因的GBM中CHI3L1的表达 小鼠模型导致肿瘤浸润性淋巴细胞(TIL)增加，肿瘤体积缩小，并有所改善 动物存活，这被CHI3L1的过度表达逆转。我们发现的潜在机制是 Galectin-3(Galectin-3)，β-半乳糖苷结合凝集素家族的成员，以及Galectin-3结合蛋白 (Gal3BP)是一种分泌型糖蛋白，与CHI3L1上的相同结合基序竞争性相互作用，导致 促肿瘤M2样与抗肿瘤M1样骨髓巨噬细胞的选择性聚集 (BMDM)和常驻小胶质细胞(MG)。此应用程序的总体目标是确定详细的 CHI3L1重置肿瘤相关巨噬细胞(TAM)的分子机制 Mg，GBM TME的主要成分，并出于治疗目的干预这一过程。中环 假说是CHI3L1与Gal3和Gal3BP结合，重新编程的招募，极化， 以及细胞因子的产生，它失调了抗肿瘤TIL的渗透和激活，以促进GBM的生长。 进展和对免疫治疗的抵抗力。为了检验我们的假设，我们建议1)描述机制 CHI3L1结合复合体在募集和极化中的作用2)破译CHI3L1是如何重新编程的 TAMS介导GBM免疫抑制，以及3)评估破坏CHI3L1结合的临床前疗效 促进GBM对免疫检查点阻断的反应的复合体。为了实现这些目标，我们将 用体外和体内获得/丧失功能的方法阐明CHI3L1结合复合体是如何调节的 免疫逃避中的TAM和TIL。为了推动翻译研究的潜在方向，我们将测试一个 新开发的多肽单独和联合免疫检查点抑制剂治疗临床前 小鼠脑胶质瘤模型。本申请中提出的研究具有创新性，因为它基于一种新的 CHI3L1结合络合物调节GBM免疫抑制的机制拟议的研究是 意义重大，因为它有望为开发有效的治疗方法提供强有力的科学依据 适用于GBM患者。最终，这样的知识有可能为癌症提供新的机会。 治疗。

Project Summary Glioblastoma (GBM) is the most common and lethal brain tumor with a median survival rate of about 15 months despite intensive multimodal treatment including immunotherapy. GBM is highly immunosuppressive and resistant to immunotherapy because glioma cells escape from effective antitumor immunity by modifying the tumor microenvironment (TME). Owing to the diversity and plasticity of tumor cells and the surrounding TME, understanding the mechanisms of immune evasion by GBM remains elusive. Our long-term goal is to dissect cancer-cell-intrinsic mechanisms that reprogram the TME of GBM for the development of effective treatments. We recently identified Chitinase-3-like-1 (CHI3L1), a highly expressed and secreted glycoprotein in GBM as a candidate to mediate immune evasion. Our central finding is that silencing Chi3l1 expression in syngeneic GBM mouse models results in increased tumor-infiltrating lymphocytes (TILs), tumor size reduction, and improved animal survival, which is reversed by overexpression of CHI3L1. The underlying mechanism we discovered is that Galectin-3 (Gal3), a member of the β-galactoside-binding lectin family, and Galectin-3 binding protein (Gal3BP), a secreted glycoprotein, interact competitively with the same binding motif on CHI3L1, leading to selective accumulation of protumor M2-like versus antitumor M1-like bone marrow-derived macrophages (BMDMs) and resident microglia (MG). The overall objective in this application is to determine the detailed molecular mechanisms whereby CHI3L1 resets tumor-associated macrophages (TAMs) including BMDMs and MG, a main component of the GBM TME, and to intervene in this process for therapeutic purposes. The central hypothesis is that CHI3L1-binding complexes with Gal3 and Gal3BP, reprogram TAM recruitment, polarization, and cytokine production, which dysregulates antitumor TIL infiltration and activation to facilitate GBM growth, progression, and resistance to immunotherapy. To test our hypothesis, we propose to 1) delineate mechanisms of CHI3L1-binding complexes in TAM recruitment and polarization; 2) decipher how CHI3L1-reprogrammed TAMs mediate GBM immunosuppression, and 3) assess the preclinical efficacy of disrupting CHI3L1-binding complexes in promoting GBM response to immune checkpoint blockade. To accomplish these aims, we will employ in vitro and in vivo gain/loss-of-function approaches to elucidate how CHI3L1-binding complexes regulate the TAMs and TILs in immune evasion. To advance a potential direction for translational research, we will test a newly-developed peptide alone and in combination therapy with immune checkpoint inhibitors in preclinical glioma mouse models. The research proposed in this application is innovative because it is based on a new mechanism of CHI3L1-binding complexes regulating GBM immunosuppression. The proposed research is significant because it is expected to provide a strong scientific rationale for the development of effective therapies for GBM patients. Ultimately, such knowledge has the potential of offering new opportunities for cancer treatment.