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

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.

LLT1-CD161 Interaction in Cancer: Promises and Challenges

“…The detection of LLT1 on GC B cells in these active mature TLS therefore supports a prognostic role of LLT1, consistent with the reported association with favorable outcome in NSCLC (54). TLS high tumors have been characterized by an increased proportion of activated effector/ memory CD8 + T cells and early differentiated, activated and nonregulatory CD4 + T cells (122,123). CD161 being expressed on effector/memory CD4 + and CD8 + T cells and being associated with better clinical outcome (54,79), these observations highlight the relevance of LLT1 and CD161 as biomarkers of active antitumor B cell and T cell immune responses.…”

B Cell Orchestration of Anti-tumor Immune Responses: A Matter of Cell Localization and Communication

“…Although dendritic cells are the major APCs that provide initial T cell activation in the lymph nodes, antigen-presenting B cells can contribute to additional CD4 + T cell expansion intratumorally, as demonstrated by ex vivo co-culture assays ( Bruno et al, 2017 ; Rossetti et al, 2018 ). Accordingly, in lung tumors, a high density of TLS B cells was associated with increased CD4 + T cell receptor repertoire clonality ( Zhu et al, 2015 ) and with a reduced percentage of Tregs ( Germain et al, 2021 ). The capacity of B cells to cross-present antigens to CD8 + T cells is also well established ( Heit et al, 2004 ; Hon et al, 2005 ; Marino et al, 2012 ) and has been demonstrated in the context of the cancer testis antigen NY-ESO-1 ( Gnjatic et al, 2003 ).…”

Case Report: Sarcoid-Like Reactions and Tertiary Lymphoid Structures Following Dual Checkpoint Inhibition in a Patient with Early-Stage Lung Adenocarcinoma

“…And tumor-infiltrating follicular regulatory T cells, which are primarily located within TLSs and exhibit superior suppressive capacity and in vivo persistence as compared with Treg cells, could impair the survival of patients and impede the efficacy of immunotherapy treatment by regulating TLS ( 32 ). Nevertheless, a retrospective study showed that high TLS-B cell density could counterbalance the deleterious impact of high Treg cell density on survival of untreated NSCLC patients ( 33 ). It is difficult to fully assess TLSs and Treg cells by biopsy before neoadjuvant immunotherapy, while Treg cells in the posttreatment tumor tissue of this patient were deemed to impair anti-tumor immune response.…”