Abstract 4442: Dual benefit of MALT1 blockade in glioblastoma

Abstract

Abstract Background: Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor. Despite advances in treatment modalities, GBM remains largely incurable and new treatment approaches are desperately needed. An innovative strategy for cancer therapy is to combine the inhibition of cancer cell-intrinsic oncogenic signaling with cancer cell-extrinsic immunological activation of the tumor microenvironment (TME). MALT1 represents a candidate target whose inhibition may provide this dual benefit. Originally identified as a proto-oncoprotein in lymphoma, MALT1 has recently also been implicated in multiple solid tumors, including GBM, and significant effort has been made to develop MALT1 protease inhibitors as anti-cancer agents. Interestingly, blockade of MALT1 protease has also been shown to selectively reprogram tumor infiltrating Treg cells into antitumor effector cells. Based on these observations, we hypothesized that in GBM, MALT1 acts both within tumor cells and within cells of the TME to promote tumorigenesis and MALT1 inhibitor treatment could thus have dual benefit. Methods/Results: We assembled a panel of mouse and human GBM cell lines and performed western-blot analysis to show that these cells demonstrate constitutive MALT1 expression and proteolytic activity. MALT1 blockade in GBM cells, using siRNA or MALT1 protease inhibitors, reduces viability and clonogenic potential, suggesting that inhibition of MALT1 could impair tumor cell survival. Single-cell RNAseq data from public datasets demonstrated that myeloid cells have the highest MALT1 expression in the GBM TME. Our data indicate that co-culture of macrophages with GBM cells induces MALT1-NF-κB activation within the macrophages and this is associated with polarization towards an M2-like immunosuppressive phenotype. Additionally, treating primary human or mouse macrophages with MALT1-protease inhibitor prevents GBM-induced M2-polarization, increases M1-polarization and enhances GBM cell killing. In a syngeneic orthotopic mouse model, GBM tumor growth is impaired, and survival is extended when tumor cells are implanted into MALT1-protease dead (PD) host mice (mice which harbor a point mutation in the MALT1-protease catalytic cysteine) as compared to when implanted into wild-type host mice. MALT1-PD mice demonstrate a less immunosuppressive GBM TME with increased M1-macrophages and decreased M2-macrophages, MDSCs and Tregs. Taken together, our findings suggest that inhibiting MALT1 protease in TME cells promotes anti-tumor immunity against brain tumors. Conclusions: Our studies suggest MALT1 protease as a new therapeutic target in GBM whose inhibition could have dual benefit via both direct effect on tumor cells and by reversing the immunosuppressive TME. Citation Format: Juliana Hofstatter Azambuja, Saigopalakrishna S. Yerneni, Gabriela N. Debom, Lisa M. Maurer, Hannah E. Butterfield, Linda R. Klei, Gary Kohanbash, Peter C. Lucas, Linda M. McAllister-Lucas. Dual benefit of MALT1 blockade in glioblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4442.