Role of B cells in anti-PD-(L)1 therapy in tumor bearing mice

Abstract

Objective To investigate the effect of tumor-infiltrating B cells on the therapeutic efficacy of programmed death ligand-1 [PD-(L)1] inhibitors and elucidate the potential mechanisms. Methods Based on immunotherapy cohorts for melanoma patients in public databases, the relationship of B cells with progression-free survival (PFS) and response to immune checkpoint inhibitors treatment was analyzed. TC-1 and B16-OVA cells were implanted subcutaneously and in the liver in 6-8-week-old female C57BL/6 mice to establish tumor xenograft models. The effect of B cell clearance on PD-(L)1 therapy was compared. Flow cytometry was performed on the 15th day of TC-1 tumor microenvironment (TME) to confirm the number, function and phenotypic changes of T cells. Flow cytometry and quantitative real-time polymerase chain reaction (qPCR) were used to detect B cell surface molecules and cytokines. Results Based on ERP105482 data from the ICBatlas public database, high CD19 expression in the tumors was associated with longer PFS in melanoma patients (753 vs 95 d, HR=0.3, 95%CI: 0.13~0.65, P=0.003). B cells were significantly enriched in immunotherapy-responsive patients (P=0.01). In a mouse TC-1 liver-loaded tumor model, PD-(L)1 antibody treatment reduced tumor mass (P < 0.01), whereas B-cell clearance attenuated the therapeutic efficacy. B cells enhanced PD-(L)1 antibody treatment by promoting T cell infiltration and function, and the treatment resulted in changes in B cell subsets, as evidenced by an increase in PD-1 low-expressing subsets (P < 0.01). Conclusion After PD-(L)1 treatment, a decrease in PD-1 expression on B cell subsets might be one of the potential mechanisms by which B cells enhance the efficacy of PD-(L)1 therapy.

Keywords

• programmed cell death ligand 1
• programmed cell death 1
• b cells
• tumor microenvironment
• immune checkpoint inhibitors