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Background: The tumor microenvironment (TME) and tertiary lymphoid structures (TLS) affect the occurrence and development of cancers. How the immune contexture interacts with the phenotype of clear cell renal cell carcinoma (ccRCC) remains unclear. Methods: We identified and evaluated TLS clusters in ccRCC using machine learning algorithms and the 12-chemokine gene signature for TLS. Analyses for functional enrichment, DNA variation, immune cell distribution, association with independent clinicopathological features and predictive value of CXCL13 in ccRCC were performed. Results: We found a prominently enrichment of the 12-chemokine gene signature for TLS in patients with ccRCC compared with other types of renal cell carcinoma. We identified a prognostic value of CCL4, CCL5, CCL8, CCL19 and CXCL13 expression in ccRCC. DNA deletion of the TLS gene signature significantly predicted poor outcome in ccRCC compared with amplification and wild-type gene signature. We established TLS clusters (C1–4) and observed distinct differences in survival, stem cell-like characteristics, immune cell distribution, response to immunotherapies and VEGF-targeted therapies among the clusters. We found that elevated CXCL13 expression significantly predicted aggressive progression and poor prognosis in 232 patients with ccRCC in a real-world validation cohort. Conclusion: This study described a 12-chemokine gene signature for TLS in ccRCC and established TLS clusters that reflected different TME immune status and corresponded to prognosis of ccRCC. We confirmed the dense presence of TILs aggregation and TLS in ccRCC and demonstrated an oncogenic role of CXCL13 expression of ccRCC, which help develop immunotherapies and provide novel insights on the long-term management of ccRCC. [ABSTRACT FROM AUTHOR]

Immunotherapy has experienced remarkable growth recently. Tertiary lymphoid structures (TLSs) and B cells may play a key role in the immune response and have a survival benefit in some solid tumors, but there have been no reports about their role in endometrial cancer (EC). We investigated the clinicopathological and pathobiological characteristics of the tumor microenvironment (TME) in EC. Patients with EC at Kyoto University Hospital during 2006–2011 were retrospectively included. In 104 patients with EC who met study inclusion criteria, 81 (77.9%) had TLSs, which consisted of areas rich in CD20+ B cells, CD8+ T cells, CD4+ T cells, and CD38+ plasma cells. The absence of TLS was independently associated with tumor progression (HR, 0.154; 95% CI, 0.044–0.536; P = 0.003). Patients with TLSs that included CD23+ germinal centers had better PFS. All tumor infiltrating lymphocytes were counted in the intratumor site. The number of CD20+ B cells was significantly larger in patients with TLSs than in those without TLS (P < 0.001). CD20+ B cells numbers were positively correlated with other TLSs. The larger number of CD20+ B cell was associated with better PFS (P = 0.015). TLSs and B cell infiltration into tumors are associated with favorable survival outcomes in patients with EC. They may represent an active immune reaction of the TME in endometrial cancer. [ABSTRACT FROM AUTHOR]

Combining different standard therapies with immunotherapy for the treatment of solid tumours has proven to yield a greater clinical benefit than when each is applied separately; however, the percentage of complete responses is still far from optimal, and there is an urgent need for improved treatment modalities. The latest literature data suggest that tertiary lymphoid structures (TLS), previously shown to correlate with the severity of autoimmune diseases or transplant rejection, are also formed in tumours, have a significant beneficial effect on survival and might reflect the generation of an effective immune response in close proximity to the tumour. Thus, the facilitation of TLS formation in tumour stroma could provide novel means to improve the efficiency of immunotherapy and other standard therapies. However, little is known about the mechanisms regulating the formation of tumour-associated TLS. Studies of chronic inflammatory diseases and transplant rejection have demonstrated that TLS formation and/or function requires the presence of B cells. Additionally, the infiltration of B cells into the tumour stroma has been demonstrated to be a significant prognostic factor for improved survival in different human tumours. This suggests that B cells could play a beneficial role in anti-tumour immune response not only in the context of antibody production, antigen presentation and Th1-promoting cytokine production, but also TLS formation. This review focuses on the latest discoveries in tumour-infiltrating B cell functions, their role in TLS formation and relevance in human tumour control, revealing novel opportunities to improve cancer therapies. [ABSTRACT FROM AUTHOR]