CD20(+)CD22(+)ADAM28(+) B Cells in Tertiary Lymphoid Structures Promote Immunotherapy Response

BACKGROUND: As the indication for immunotherapy is rapidly expanding, it is crucial to accurately identify patients who are likely to respond. Infiltration of B cells into many tumor types correlates with a good response to immune checkpoint inhibitor (ICI) therapy. However, B cells’ roles in the anti-tumor response are far from clear. METHODS: Based on single-cell transcriptomic data for ICI-treated patients, we identified a B-cell cluster [B(IR) (ICI-Responsive B) cells] and described the phenotype, cell–cell communication, biological processes, gene signature, and prognosis value of B(IR) cells through bioinformatic analysis, tissue immunofluorescence, and animal experiments. Surgery samples from 12 non-small cell lung carcinoma (NSCLC) patients with adjuvant checkpoint blockade were evaluated as external validation. RESULTS: B(IR) cells were identified as a subset of CD20(+)CD22(+)ADAM28(+) B cells with a memory phenotype. Bioinformatic analysis revealed that B(IR) cells had enhanced cell viability and epigenetic regulation, and that ALOX5AP, MIF, and PTPRC/CD45 expressed by myeloid cells may be critical coordinators of diverse biological processes of B(IR) cells. Immunofluorescence confirmed the presence of B(IR) cells in tertiary lymphoid structures (TLSs) in skin SCC, RCC, CRC, and breast cancer. B(IR)-associated gene signatures correlate with positive outcomes in patients with melanoma, glioblastoma, NSCLC, HNSCC, or RCC treated with ICI therapy, and B(IR)-cell density predicted NSCLC patients’ response to checkpoint immunotherapy. In line with this, melanoma-bearing mice depleted of B(IR) cells were resistant to ICIs. CONCLUSIONS: CD20(+)CD22(+)ADAM28(+) B(IR) cells were present in cancer-associated TLS and promoted the response to ICI therapy.