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 a… Show more
“…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.…”
Section: Elfs As Regulators Of Anti‐tumour Immunitymentioning
confidence: 54%
“…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).…”
Section: Elfs As Regulators Of Anti‐tumour Immunitymentioning
SummaryLymphoid neogenesis is traditionally viewed as a pre‐programmed process that promotes the formation of lymphoid organs during development. Here, the spatial organization of T and B cells in lymph nodes and spleen into discrete structures regulates antigen‐specific responses and adaptive immunity following immune challenge. However, lymphoid neogenesis is also triggered by chronic or persistent inflammation. Here, ectopic (or tertiary) lymphoid organs frequently develop in inflamed tissues as a response to infection, auto‐immunity, transplantation, cancer or environmental irritants. Although these structures affect local immune responses, the contribution of these lymphoid aggregates to the underlining pathology are highly context dependent and can elicit either protective or deleterious outcomes. Here we review the cellular and molecular mechanisms responsible for ectopic lymphoid neogenesis and consider the relevance of these structures in human disease.
“…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.…”
Section: Elfs As Regulators Of Anti‐tumour Immunitymentioning
confidence: 54%
“…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).…”
Section: Elfs As Regulators Of Anti‐tumour Immunitymentioning
SummaryLymphoid neogenesis is traditionally viewed as a pre‐programmed process that promotes the formation of lymphoid organs during development. Here, the spatial organization of T and B cells in lymph nodes and spleen into discrete structures regulates antigen‐specific responses and adaptive immunity following immune challenge. However, lymphoid neogenesis is also triggered by chronic or persistent inflammation. Here, ectopic (or tertiary) lymphoid organs frequently develop in inflamed tissues as a response to infection, auto‐immunity, transplantation, cancer or environmental irritants. Although these structures affect local immune responses, the contribution of these lymphoid aggregates to the underlining pathology are highly context dependent and can elicit either protective or deleterious outcomes. Here we review the cellular and molecular mechanisms responsible for ectopic lymphoid neogenesis and consider the relevance of these structures in human disease.
“…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.…”
Section: Introductionmentioning
confidence: 99%
“…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.…”
Tertiary lymphoid structures (TLSs) display phenotypic and functional characteristics of secondary lymphoid organs, and often develop in tissues affected by chronic inflammation, as well as in certain inflammation‐associated cancers where they are prognostic of improved patient survival. However, the mechanisms that govern the development of tumour‐associated TLSs remain ill‐defined. Here, we observed tumour‐associated TLSs in a preclinical mouse model (gp130
F/F) of gastric cancer, where tumourigenesis is dependent on hyperactive STAT3 signalling through the common IL‐6 family signalling receptor, gp130. Gastric tumourigenesis was associated with the development of B and T cell‐rich submucosal lymphoid aggregates, containing CD21+ cellular networks and high endothelial venules. Temporally, TLS formation coincided with the development of gastric adenomas and induction of homeostatic chemokines including Cxcl13, Ccl19 and Ccl21. Reflecting the requirement of gp130‐driven STAT3 signalling for gastric tumourigenesis, submucosal TLS development was also STAT3‐dependent, but independent of the cytokine IL‐17 which has been linked with lymphoid neogenesis in chronic inflammation and autoimmunity. Interestingly, upregulated lymphoid chemokine expression and TLS formation were also observed in a chronic gastritis model induced by Helicobacter felis infection. Tumour‐associated TLSs were also observed in patients with intestinal‐type gastric cancer, and a gene signature linked with TLS development in gp130
F/F mice was associated with advanced clinical disease, but was not prognostic of patient survival. Collectively, our in vivo data reveal that hyperactive gp130‐STAT3 signalling closely links gastric tumourigenesis with lymphoid neogenesis, and while a TLS gene signature was associated with advanced gastric cancer in patients, it did not indicate a favourable prognosis.
“…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.…”
T follicular helper cells (Tfh) play crucial roles in the development of humoral immunity. In the B cell-rich germinal center of lymphoid organs, they select for high-affinity B cells and aid in their maturation. While Tfh have known roles in B cell malignancies and have prognostic value in some epithelial cancers, their role in lung tumour initiation and development is unknown. Through immune cell deconvolution, we observed significantly increased Tfh in tumours from two independent cohorts of lung adenocarcinomas and found that this upregulation occurs early in tumour development. A subset of tumours were stained for T and B cells using multicolour immunohistochemistry, which revealed the presence of tumour-adjacent tertiary lymphoid organs in 17/20 cases each with an average of 16 Tfh observed in the germinal center. Importantly, Tfh levels were correlated with tumour mutational load and immunogenic cancer testis antigens, suggesting their involvement in mounting an active immune response against tumour neoantigens.
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