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

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.

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.

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.

CD20⁺CD22⁺ADAM28⁺ B_IR cells were present in cancer-associated TLS and promoted the response to ICI therapy.