Hou D, Wang S, Castro BA, Katz JL, Dapash M, Arrieta VA, Vazquez-Cervantes GI, Wan H, Billingham LK, Du R, Murphy AR, Lopez-Rosas A, Han Y, Patel RV, Chia TY, Dmello CC, Zhang P, Sheppard D, Sonabend AM, Miska JM, Lesniak MS, Heiland DH, Lee-Chang C (2025)
Publication Type: Journal article
Publication year: 2025
Book Volume: 27
Pages Range: 2355-2369
Journal Issue: 9
Background. Immunotherapy has revolutionized cancer treatment but has yet to be translated into brain tumors. Studies in other solid tumors suggest a central role of B-cell immunity in driving immune checkpoint blockade efficacy. In glioblastoma (GBM), tumor B cells are driven into a regulatory B-cell state that suppresses immune activation and T-cell function. Methods. We used spatially resolved transcriptomics and multiplex immunofluorescence to characterize B-cell neighborhoods within GBM and identify enhanced TGFβ-signaling between myeloid and B cells. We generated conditional knockouts to investigate the effects of TGFβ signaling on B-cell function and survival in vivo. Additionally, we combined TGFβ blockade with PD-1 inhibition to evaluate their combined anti-glioma efficacy. Results. Our findings reveal that myeloid cells are the primary interactors with B cells in GBM through the TGFβ pathway. Pharmacological or genetic TGFβ blockade expanded intratumoral B cells and synergized with PD-1 inhibition to enhance survival (60% tumor eradication in dual-treated mice). Therapeutic efficacy critically depended on B cells, as their depletion abolished survival benefits. Dual αVβ8/PD-1 blockade reduced B-cell-mediated suppression of CD8⁺ T-cell cytotoxicity and increased plasmablast differentiation, while partial efficacy in RagKO mice implicated ancillary roles for innate immunity. Conclusion. Targeting TGFβ signaling using an anti-αVβ8 blocker can impact anti-tumor immunity through different possible mechanisms, of which we highlight the rescuing of B-cell function through synergy with PD-1 checkpoint blockade therapy. Our work underscores the critical role of intratumoral B-cell immunity in enhancing immunotherapy against brain tumors.
APA:
Hou, D., Wang, S., Castro, B.A., Katz, J.L., Dapash, M., Arrieta, V.A.,... Lee-Chang, C. (2025). Dual aVß8 Integrin and PD-1 Blockade Overcomes TGFβ-Mediated B-Cell Suppression to Enhance Anti-Tumor Immunity. Neuro-Oncology, 27(9), 2355-2369. https://doi.org/10.1093/neuonc/noaf106
MLA:
Hou, David, et al. "Dual aVß8 Integrin and PD-1 Blockade Overcomes TGFβ-Mediated B-Cell Suppression to Enhance Anti-Tumor Immunity." Neuro-Oncology 27.9 (2025): 2355-2369.
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