Abstract
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-Bhigh 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-Bhigh Treglow patients had the best clinical outcomes. Overall, the correlation between the density of TLS-Bhigh 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.
Highlights
The tumor microenvironment is marked by its complexity and substantial amount of heterogeneity
As our previous study showed that the presence of tertiary lymphoid structures (TLS)-B cells in the tumor microenvironment mainly favors intratumor CD4+ T cell clonal expansion [13], we analyzed the expression of 550 immune-related genes in sorted tumor-infiltrating lymphocyte (TIL) CD4+ T cells from 26 non-small cell lung cancer (NSCLC) patients in relation to their TLS-B cell densities
TLS-B cell density was correlated with 11 genes expressed by TIL CD4+ T cells (Supplementary Figure 4A)
Summary
The tumor microenvironment is marked by its complexity and substantial amount of heterogeneity. Studies have shown that while high densities of TIL CD8+ T cells or TIL B cells are associated with better survival in some cancers, other immune subsets, such as regulatory T cells (Tregs), are mostly associated with poor clinical outcomes [1,2,3]. High TLS density is most often associated with better clinical outcomes [4, 9,10,11]. We have previously shown that high densities of TLS-DC or TLSB cells are associated with prolonged survival in non-small cell lung cancer (NSCLC) [2, 5, 12], and that TLS-B cellhigh tumors are linked to the development of tumor antigenspecific antibodies [2] and increased TIL CD4+ T cell repertoire clonality [13]
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