Antigen-presenting B cells promote TCF-1+ PD1- stem-like CD8+ T-cell proliferation in glioblastoma

作者：David Hou, Hanxiao Wan, Joshua L. Katz, Si Wang, Brandyn Castro, Gustavo Vazquez-Cervantes, Víctor A. Arrieta, Silpol Dhiantravan, Hinda Najem, Aida Rashidi, Tzu-Yi Chia, Tarlan Arjmandi, Jimena Collado, Leah Billingham, Aurora Lopez‐Rosas, Yu Han, Adam M. Sonabend, Amy B. Heimberger, Peng Zhang, Jason Miska, Catalina Lee-Chang · 发表于：Frontiers in Immunology · 年份：2024 · DOI：10.3389/fimmu.2023.1295218 · 被引用次数：12 · 研究领域：Immunotherapy and Immune Responses、CAR-T cell therapy research、Cancer Immunotherapy and Biomarkers

Understanding the spatial relationship and functional interaction of immune cells in glioblastoma (GBM) is critical for developing new therapeutics that overcome the highly immunosuppressive tumor microenvironment. Our study showed that B and T cells form clusters within the GBM microenvironment within a 15-μm radius, suggesting that B and T cells could form immune synapses within the GBM. However, GBM-infiltrating B cells suppress the activation of CD8 + T cells. To overcome this immunosuppression, we leveraged B-cell functions by activating them with CD40 agonism, IFNγ, and BAFF to generate a potent antigen-presenting B cells named B Vax . B Vax had improved antigen cross-presentation potential compared to naïve B cells and were primed to use the IL15-IL15Ra mechanism to enhance T cell activation. Compared to naïve B cells, B Vax could improve CD8 T cell activation and proliferation. Compared to dendritic cells (DCs), which are the current gold standard professional antigen-presenting cell, B Vax promoted highly proliferative T cells in-vitro that had a stem-like memory T cell phenotype characterized by CD62L + CD44 - expression, high TCF-1 expression, and low PD-1 and granzyme B expression. Adoptive transfer of B Vax -activated CD8 + T cells into tumor-bearing brains led to T cell reactivation with higher TCF-1 expression and elevated granzyme B production compared to DC-activated CD8 + T cells. Adoptive transfer of B Vax into an irradiated immunocompetent tumor-bearing ho...