Memory B cell subset shapes antitumor immunity and response to PD-1 blockade in mismatch repair-deficient colorectal...

Mismatch repair deficiency (dMMR) colorectal cancer (CRC) is characterized by abundant tumor-infiltrating lymphocytes and tertiary lymphoid structures (TLSs). However, while B cells are pivotal for TLS formation, their function and the signaling pathways driving their activation in dMMR CRCs remain undefined.

Data from The Cancer Genome Atlas (TCGA) database analyzed by XCELL method and multiplex immunofluorescence (MIF) staining tissue slides were used to compare the abundance and distribution of TLSs and B cell populations between dMMR and proficient MMR cohorts. Then MLH1 knockdown models both in vitro and in vivo were used to mimic dMMR/high microsatellite instability (MSI-H) tumors and explore the influence of tumor cells on B cell behavior.

TCGA analysis and MIF staining revealed a significant association between memory B cell abundance, TLS formation, and improved prognosis in dMMR CRCs. In vivo MLH1 knockdown models showed that B cell depletion enhanced tumor growth and reduced the efficacy of anti-PD-1 treatment in dMMR CRCs. Furthermore, in vitro experiments demonstrated a dsDNA/STING/type I interferon (IFN)/STAT1/ccl19 signaling pathway mediating the dMMR-induced increase in memory B cells.

In conclusion, these findings show that CCL19 generated by STING/type I IFN/STAT1 pathway in dMMR/MSI-H CRC cells can promote the expansion of memory B cells, which suppresses tumor growth and enhances the efficacy of PD-1 blockade.