Dendritic cells control the formation, maintenance & function of tertiary lymphoid structures in cancer.

Abstract

Tertiary lymphoid structures (TLS) correlate with favorable responses to immunotherapy, yet the mechanisms governing their formation and maintenance in tumors remain poorly defined. Through high-resolution spatial mapping across human tumors, we identified a consistent accumulation of CCR7⁺ mature dendritic cells (DCs) within TLS. To dissect their function, we developed a novel non-small cell lung cancer (NSCLC) model that recapitulates mature TLS formation. Using this model, we demonstrate that TLS induction requires IFNγ-driven maturation of type 1 conventional dendritic cells (cDC1), their migration to tumor-draining lymph nodes (TdLNs), and the subsequent recruitment of TdLN-primed T cells into the tumor microenvironment. As tumors advance, TLS persist even in the absence of TdLN T cell egress, coinciding with impaired cDC1 migration to TdLNs and their retention within intratumoral stromal hubs enriched in CCR7 ligands. Timed depletion of cDC1 or blockade of their localization to these hubs disrupts TLS maintenance. Strikingly, genetic ablation of both MHC class I and II on cDC1 abolishes the maintenance of TLS, T follicular helper (T FH ) cells, germinal center formation, tumor-specific IgG production, and the differentiation of progenitor exhausted CD8⁺ T cells.
These findings establish that local cDC1-mediated activation of CD8⁺ and CD4⁺ T cells are central orchestrators of anti-tumor TLS programs and compelling targets for therapeutic intervention.

Brief biography

Raphael Mattiuz is an AACR postdoctoral fellow in Dr. Miriam Merad’s lab at the Icahn School of Medicine at Mount Sinai (New York), where he investigates how dendritic cells (DCs) orchestrate the formation and maintenance of tertiary lymphoid structures (TLS) in cancer. He completed his PhD at the Centre d’Immunologie de Marseille-Luminy (CIML) in the laboratory of Dr. Marc Dalod, focusing on cDC1-mediated control of T cell responses in breast cancer immunosurveillance. Prior to that, he trained in mucosal immunology and epigenetics at Institut Cochin (Paris) and the Babraham Institute (Cambridge, UK).
He has also contributed to recent studies on the role of aging and IL-4 signaling in myelopoiesis and macrophage dysfunction in lung cancer. His future research aims to dissect how myeloid cells regulate TLS functionality and local immune memory across cancer, infection, and chronic inflammatory diseases.