It is now well established that immune responses can take place at distance of secondary lymphoid organs, in tertiary lymphoid structures (TLS). We have previously shown that such structures can develop in human lung cancer (LC), and may represent an activation site for tumor-specific T cells. The aim of this study was to determine whether a protective adaptive immunity can take place within TLS.
We showed that the density of TLS is associated with a specific immune signature. Some genes related to chemotaxis (adhesion molecules, chemokines and integrins) are overexpressed in TLS, and correlated with T cell density. Intra-tumoral PNAd+ high endothelial venules were exclusively associated with TLS, and colocolized with CD62L+ T cells in TLS. Moreover, the density of TLS is associated with the coordination of T-cell immune response. Tumors with high density of TLS present a specific immune contexture characterized by a strong T-cell infiltration, T-cell activation with a Th1 polarization and cytotoxic effector function.
Regarding the humoral immunity, we have observed that B-cell follicles of TLS present the same cellular composition and organization as in lymph nodes, with all B-cell differentiation stages. The somatic mutation and isotype switching machineries were activated in these B-cell follicles. The PNAd+ ligand CD62L, was selectively detected on TLS B cells except by germinal center B-cells, as reported for lymph nodes. CXCR5 expression decreased on fully differentiated B cells, a known key regulatory process that allows effector cells to leave CXCL13+ germinal centres. In a retrospective study, the density of TLS B cells was associated with a favorable clinical outcome in patients with early-stage LC. More interestingly, combination of both markers of APC (mature dendritic and B cells of TLS), indicated that they are strongly correlated with long-term survival for patients with early-stage LC and patients with advanced-stage of LC treated by neo-adjuvant-chemotherapy. Preliminary data on the specificity of antibodies secreted locally by intra-tumoral B cells will be discussed in the physiopathology of human LC.
Altogether, these data bring new insights into the lymphocyte recruitment to intra-tumoral TLS, and suggest that peripheral blood T and B cells enter into TLS via high endothelial venules, which represent a new gateway for lymphocytes to the tumor. TLS may represent an active site for the initiation of a protective cellular and humoral immunity. In this immunosuppressive situation, TLS may play a major role in the shaping of the intra-tumoral immune contexture.
Disclosure of Interest None Declared
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