Tertiary Lymphoid Structure-B Cells Narrow Regulatory T Cells Impact in Lung Cancer Patients

The presence of tertiary lymphoid structures (TLS) in the tumor microenvironment is associated with better clinical outcome in many cancers. In non-small cell lung cancer (NSCLC), we have previously showed that a high density of B cells within TLS (TLS-B cells) is positively correlated with tumor antigen-specific antibody responses and increased intratumor CD4⁺ T cell clonality. Here, we investigated the relationship between the presence of TLS-B cells and CD4⁺ T cell profile in NSCLC patients. The expression of immune-related genes and proteins on B cells and CD4⁺ T cells was analyzed according to their relationship to TLS-B density in a prospective cohort of 56 NSCLC patients. We observed that tumor-infiltrating T cells showed marked differences according to TLS-B cell presence, with higher percentages of naïve, central-memory, and activated CD4⁺ T cells and lower percentages of both immune checkpoint (ICP)-expressing CD4⁺ T cells and regulatory T cells (Tregs) in the TLS-B^high tumors. A retrospective study of 538 untreated NSCLC patients showed that high TLS-B cell density was even able to counterbalance the deleterious impact of high Treg density on patient survival, and that TLS-B^high Treg^low patients had the best clinical outcomes. Overall, the correlation between the density of TLS-B^high tumors with early differentiated, activated and non-regulatory CD4⁺ T cell cells suggest that B cells may play a central role in determining protective T cell responses in NSCLC patients.