Anti-VEGF treatment potentiates ICB responses through a BAFF and IL-12-dependent reprogramming of the TME

Anti-VEGF treatment has shown clinical activity in combination with checkpoint inhibitor therapy, but the exact mechanism is not known. We show that adding VEGF blockade to the ICB combination of anti-CTLA4 + anti-PD-L1 in cholangiocarcinoma unleashed a therapeutic efficacy driven through a novel multimodal mechanism dependent on BAFF production by T and myeloid cells, leading to a BAFF-dependent proinflammatory B cell response characterized by Germinal center B cell and plasma cell expansion, as well as IL-12 production. Using single cell RNA sequencing (scRNA-Seq) of paired pre- and post-treatment tumor biopsy samples from patients treated with anti-CTLA4, anti-PD-L1 and anti-VEGF, we characterized the treatment-associated immunological changes. Overall design: We performed single cell RNA sequencing (scRNA-Seq) of liver cancer tumor biopsy samples (pre- and post-treatment) from three patients that contributed a total of seven samples (paired pre- and post- treatment samples from patients 1 and 2, and one pre-treatment and two post-treatment samples from patient 3).