Tertiary lymphoid structures in Merkel cell carcinoma facilitate naïve and central memory T-cell infiltration linked to immunotherapy response.

backgroundThe presence of tertiary lymphoid structures (TLS) in solid tumors, including Merkel cell carcinoma (MCC), is associated with a better prognosis and a better response to immunotherapy with immune checkpoint inhibition (ICI). The detailed mechanisms by which TLS influence antitumor immune responses are only partially understood.

methodsClinically annotated tumor tissues of 27 patients with MCC were obtained prior to ICI therapy. Tumor samples were subjected to transcriptomic and multiplex immuno-visual profiling, T-cell receptor (TCR) clonotype mapping, as well as-in selected cases-spatial transcriptomics to comprehensively characterize the tumor immune microenvironment.

resultsWeighted gene co-expression network analysis (WGCNA) of transcriptomic data in combination with topological overlap measures indicated a higher abundance of TLS in tumors of patients with MCC responding to ICI therapy. This concept was substantiated through immunomorphological analyses, revealing mature B-cell follicle-like structures characterized by high endothelial venules (HEVs). Further supporting HEVs as critical entry points for naïve T cells, the presence of TLS was correlated with a pronounced infiltration of CD4

conclusionOur findings are consistent with a key role of TLS in shaping immune interactions within the MCC microenvironment, driving the recruitment of diverse tumor-reactive T cells. These insights hold promise for advancing immunotherapeutic strategies.