Dual aVß8 Integrin and PD-1 Blockade Overcomes TGFβ-Mediated B-Cell Suppression to Enhance Anti-Tumor Immunity

  • Neuro Oncol. 2025 Oct 14;27(9):2355-2369. doi: 10.1093/neuonc/noaf106.
David Hou  1  2 ,  Si Wang  1  2 ,  Brandyn A Castro  3 ,  Joshua L Katz  1  2 ,  Mark Dapash  1 ,  Victor A Arrieta  1  2 ,  Gustavo I Vazquez-Cervantes  1  2 ,  Hanxiao Wan  1  2 ,  Leah K Billingham  1  2 ,  Rebecca Du  1 ,  Alina R Murphy  1  2 ,  Aurora Lopez-Rosas  1 ,  Yu Han  1 ,  Ronit V Patel  1 ,  Tzu-Yi Chia  1  2 ,  Crismita C Dmello  1  2 ,  Peng Zhang  1  2 ,  Dean Sheppard  4 ,  Adam M Sonabend  1  2 ,  Jason M Miska  1  2 ,  Maciej S Lesniak  1  2 ,  Dieter Henrik Heiland  1  2  5  6  7  8 ,  Catalina Lee-Chang  1  2
Affiliations
  • 1. Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
  • 2. Lou and Jean Malnati Brain Tumor Institute, Chicago, Illinois, USA.
  • 3. Department of Neurosurgery, University of Chicago, Chicago, Illinois, USA.
  • 4. Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, USA.
  • 5. Translational Neurosurgery, Alexander-Friedrich-Universität Erlangen-Nürnberg, Erlangen, Germany.
  • 6. Neurosurgical Clinic, University Clinic, Alexander-Friedrich-Universität Erlangen-Nürnberg, Erlangen, Germany.
  • 7. Comprehensive Cancer Center Freiburg (CCCF), Medical Center-University of Freiburg, Freiburg, Germany.
  • 8. German Cancer Consortium (DKTK) partner site, Freiburg, Germany.
PMID: 40269603 DOI: 10.1093/neuonc/noaf106
Abstract

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.

Keywords
B cells; TGFβ; checkpoint-blockade; glioblastoma; tumor microenvironment.