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

BackgroundAs 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. MethodsBased 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. ResultsB(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. ConclusionsCD20(+)CD22(+)ADAM28(+) B-IR cells were present in cancer-associated TLS and promoted the response to ICI therapy.