Year: 2026
Type: conference-abstract
Abstract: Background On Feb 10, 2026, the FDA approved pembrolizumab in combination with paclitaxel, with or without bevacizumab, for adult patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma whose tumors express PD-L1 with a combined positive score (CPS) ≥ 1, and who have received one or two prior systemic treatment regimens. Efficacy was evaluated in the ENGOT-ov65/KEYNOTE-B96 trial, which showed a modest benefit from pembrolizumab. There is a clear need for supplementation of checkpoint inhibitors with additional strategies that elicit new immune responses and mitigate the evolution of immunosuppressive microenvironment.Methods Earlier published work showed that (i) anti-PD-1 treatment elevated ascites IL-10 levels in ID8 tumor-bearing mice, (ii) anti-PD-1 expanded ascites B cells and plasma cells, and (iii) Th17-inducing dendritic cell (Th17-DC) vaccination blocked anti-PD-1-induced IL-10 expression and B cell expansion, while boosting responses to anti-PD-1. From these observations, we propose the paradigm-shifting concept that regulatory B cells (Breg) mediate resistance to immune checkpoint inhibition. In this study, we tested the ability of B cell depletion or selective Breg targeting to enhance responses to anti-PD-1 in multiple mouse models of ovarian cancer.Results Transient B cell depletion with anti-CD20 antibody in the ID8 p53 -/- and SO1 p53-/- BRCA1-/-/Myc/Hras models of ovarian cancer markedly enhanced overall survival following anti-PD-1 treatment. Selective targeting of Breg through treatment with anti-TIM-1 also boosted responses to anti-PD-1 in the ID8 p53-/- model, to a level comparable with B cell depletion.Conclusions This study constitutes a strategic pivot to focus on the role of B cells in resistance to anti-PD-1 immune checkpoint blockade. From a clinical perspective, enhancement of responses to pembrolizumab may be achievable through non-selective B cell depletion with existing FDA-approved agents, notably rituximab.Acknowledgements We thank Sandra Orsulic (University of California, Los Angeles) for her kind gift of the SO1 ovarian tumor cell line.Ethics Approval This study was approved by the University of Arkansas for Medical Sciences Institutional Animal Care and Use Committee, approval number IPROTO202300000055.
Institution: University of Arkansas for Medical Sciences
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225191530