Dendritic cells type 1 control the formation, maintenance, and function of tertiary lymphoid structures in cancer
Authors: Mattiuz Raphaël , Boumelha Jesse , Hamon Pauline , Le Berichel Jessica , Vaidya Abishek , Soong Brian Y. , Halasz Laszlo , Radkevich Emir , Kim Hye Mi , Park Matthew D. , Donne Romain , Troncoso Leanna , D’Souza Darwin , Kaiza Medard Ernest , MacFawn Ian P. , Belabed Meriem , Mestrallet Guillaume , Humblin Etienne , Merand Raphaël , Hennequin Clotilde , Ioannou Giorgio , Ozbey Sinem , Figueiredo Igor , Hegde Samarth , Tepper Alexander , Merarda Hajer , Nemeth Erika , Goldstein Simon , Reid Amanda M. , Noureddine Moataz , Tabachnikova Alexandra , Ahmed Jalal , Polydorides Alexandros D. , Bhardwaj Nina , Lujambio Amaia , Chen Zhihong , Gonzalez Kozlova Edgar , Kim-Schulze Seunghee , Brody Joshua D. , Schotsaert Michael , Moussion Christine , Gnjatic Sacha , Sautès-Fridman Catherine , Fridman Wolf Herman , Roudko Vladimir , Brown Brian D. , Marron Thomas U. , Cyster Jason G. , Salmon Hélène , Bruno Tullia C. , Joshi Nikhil S. , Kamphorst Alice O. , Merad Miriam 
Published: December 2024

Tertiary lymphoid structures (TLS) are organized immune cell aggregates that arise in chronic inflammatory conditions. In cancer, TLS are associated with better prognosis and enhanced response to immunotherapy, making these structures attractive therapeutic targets. However, the mechanisms regulating TLS formation and maintenance in cancer are incompletely understood. Using spatial transcriptomics and multiplex imaging across various human tumors, we found an enrichment of mature dendritic cells (DC) expressing high levels of CCR7 in TLS, prompting us to investigate the role of DC in the formation and maintenance of TLS in solid tumors. To address this, we developed a novel murine model of non-small cell lung cancer (NSCLC) that forms mature TLS, containing B cell follicles with germinal centers and T cell zones with T follicular helper cells (TFH) and TCF1+PD-1+progenitor exhausted CD8+T cells (Tpex). Here we show that, during the early stages of tumor development, TLS formation relies on IFNγ-driven maturation of the conventional DC type 1 (cDC1) subset, their migration to tumor-draining lymph nodes (tdLN), and recruitment of activated T cells to the tumor site. As tumors progress, TLS maintenance becomes independent of T cell egress from tdLN, coinciding with a significant reduction of cDC1 migration to tdLN. Instead, mature cDC1 accumulate within intratumoral CCR7 ligand-enriched stromal hubs. Notably, timed depletion of cDC1 or disruption of their migration to these stromal hubs after TLS are formed alters TLS maintenance. Importantly, we found that cDC1-mediated antigen presentation to both CD4+and CD8+T cells and intact CD40 signaling, is critical for the maintenance of TLS, the preservation of the TFHcell pool, the formation of germinal center and the production of tumor-specific IgG antibodies. These findings underscore the key role of mature cDC1 in establishing and maintaining functional TLS within tumor lesions and highlight the potential for cDC1-targeting therapies as a promising strategy to enhance TLS function and improve anti-tumor immunity in patients with cancer.