TMIC-81. Targeting TGFβ-mediated B cell suppression enhances anti-PD-1 efficacy in glioblastoma

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Abstract Immunotherapy has revolutionized cancer treatment but remains ineffective against glioblastoma (GBM), where the immunosuppressive tumor microenvironment (TME) limits therapeutic success. While B-cells influence immune checkpoint blockade (ICB) responses in peripheral tumors, their role in GBM remains poorly understood. Here, we demonstrate that myeloid-derived TGFβ signaling drives B-cell dysfunction in GBM, and dual blockade of αVβ8-mediated TGFβ activation and PD-1 synergistically enhances anti-tumor immunity. Using spatial transcriptomics and multiplex immunofluorescence, we identified myeloid-B cell crosstalk via TGFβ as a key immunosuppressive axis in GBM. Myeloid cells, particularly bone-derived macrophages, localized near B-cells and induced TGFβ1-dependent suppression, impairing B-cell expansion and function. Genetic (Tgfbr2 knockout in B cells) or pharmacological (αVβ8 blockade) TGFβ inhibition expanded intratumoral B-cells and synergized with PD-1 blockade, achieving 60% tumor eradication in murine GBM models—an effect entirely dependent on B-cells, as their depletion abolished therapeutic efficacy. Mechanistically, dual therapy rescued B-cell function, reducing their suppression of CD8⁺ T-cell cytotoxicity and promoting plasmablast differentiation. Notably, surviving mice developed immunological memory, which was lost upon B-cell depletion, highlighting their role in sustained anti-tumor immunity. Dual αVβ8/PD-1 blockade uniquely enhanced CD8⁺ T-cell proliferation and granzyme B expression while fostering a Th17-polarized CD4⁺ T-cell response. Intratumorally, plasmablast differentiation increased without systemic effects, suggesting localized immune reprogramming. Partial efficacy in RagKO mice indicated ancillary innate immune contributions, but B-cells were the dominant mediators of therapeutic response. Our findings establish TGFβ inhibition as a strategy to reverse B-cell dysfunction in GBM and demonstrate that dual αVβ8/PD-1 blockade reinvigorates anti-tumor immunity through coordinated B and T-cell activation. This work positions B-cells as pivotal targets for improving immunotherapy in GBM and supports clinical translation of integrin-based combination therapies.

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