Chitinase-3-like-1 mediated immunosuppression in Glioblastoma

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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.