Presence of B Cells in Tertiary Lymphoid Structures Is Associated with a Protective Immunity in Patients with Lung Cancer

Abstract

Rationale: It is now well established that immune responses can take place outside of primary and secondary lymphoid organs. We previously described the presence of tertiary lymphoid structures (TLS) in patients with non-small cell lung cancer (NSCLC) characterized by clusters of mature dendritic cells (DCs) and T cells surrounded by B-cell follicles. We demonstrated that the density of these mature DCs was associated with favorable clinical outcome. Objectives: To study the role of follicular B cells in TLS and the potential link with a local humoral immune response in patients with NSCLC. Methods: The cellular composition of TLS was investigated by immunohistochemistry. Characterization of B-cell subsets was performed by flow cytometry. A retrospective study was conducted in two independent cohorts of patients. Antibody specificity was analyzed by ELISA. Measurements and Main Results: Consistent with TLS organization, all stages of B-cell differentiation were detectable in most tumors. Germinal center somatic hypermutation and class switch recombination machineries were activated, associated with the generation of plasma cells. Approximately half of the patients showed antibody reactivity against up to 7 out of the 33 tumor antigens tested. A high density of follicular B cells correlated with long-term survival, both in patients with early-stage NSCLC and with advanced-stage NSCLC treated with chemotherapy. The combination of follicular B cell and mature DC densities allowed the identification of patients with the best clinical outcome. Conclusions: B-cell density represents a new prognostic biomarker for NSCLC patient survival, and makes the link between TLS and a protective B cell-mediated immunity.

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

“…In lung tumour‐associated ELFs, a high proportion of mature DCs correlate with gene signatures linked with Th1 cell activation and improved long‐term patient survival 97. Similar observations have been reported for B‐cell densities in NSCLC, where follicular B cells correlate with long‐term survival both in early‐stage disease and in advanced disease treated with chemotherapy 96. Therefore, ELF development may facilitate the recruitment of naive T and B cells from the peripheral pool via HEVs and homeostatic chemokines.…”

“…In this context, it is therefore surprising that ELFs arise in tumours at all. However, ELFs have been described in numerous cancers including colorectal,60, 88 rectal,89 breast,67, 90, 91 ovarian67, 92 and germ cell93 cancers, as well as melanoma,62, 67, 94 mucosal‐associated lymphoid tissue lymphoma39 and non‐small cell lung carcinoma95, 96 (NSCLC; see Dieu‐Nosjean et al . for a comprehensive review of ELFs in cancer9).…”

Hyperactive gp130/STAT3‐driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development

“…Tertiary lymphoid structures (TLSs; also called ectopic lymphoid structures, ELSs) are inducible lymphoid aggregates that phenotypically and functionally resemble secondary lymphoid organs 4. TLSs can develop in tissues where persistent inflammation is present, and a correlation between high TLS densities and prolonged patient survival has been reported for several cancers including breast,5, 6 lung,7, 8 melanoma,9 pancreatic10 and colorectal 11, 12. TLS gene signatures, that include homeostatic chemokines such as CXCL13 , CCL19 and CCL21 , have the potential to represent prognostic indicators of cancer progression in melanoma13 and colorectal cancer 14, 15.…”

“…For example, clonal expansion of interferon‐(IFN)‐γ producing T cells reactive to tumour antigens, which inhibit tumour growth, have been observed in experimental mouse melanoma 16, 17. Improved patient survival in non‐small‐cell lung carcinoma has also been linked with TLSs, where follicular B cells and plasma cells show antibody specificity to tumour antigens 8. However, TLS involvement and activity may only have prognostic value in certain stages of tumour development or for certain types of cancer 11, 18, 19.…”

Somatic mutation-associated T follicular helper cell elevation in lung adenocarcinoma

“…5,6 Mechanistically, this antitumour effect is associated with the activation of B cell maturation machinery and presence of tumour antigen-specific antibodies. 6 Despite the well-characterized role of infiltrating B cells and TLOs, the role of Tfh in human lung cancers remains understudied. 7 Infection models have revealed that circulating Tfh function differently from those in lymphoid tissue and correlate with opposing outcomes.…”