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© Institut Pasteur - Photo by Perrine Bomme, Lise Chauveau & Olivier Schwartz, colorized by Jean-Marc Panaud
Cellule dendritique vue en microscopie électronique à balayage. Les cellules dendritiques sont cellules importantes de l'immunité. Elles sont indispensables à la mise en place de défenses contre les agents infectieux, les tumeurs ou les maladies auto-immunes. Elles interviennent également dans les processus de tolérance de greffes.
Publication : Nature communications

Dendritic cell-targeted therapy expands CD8 T cell responses to bona-fide neoantigens in lung tumors.

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Nature communications - 13 Mar 2024

López L, Morosi LG, La Terza F, Bourdely P, Rospo G, Amadio R, Piperno GM, Russo V, Volponi C, Vodret S, Joshi S, Giannese F, Lazarevic D, Germano G, Stoitzner P, Bardelli A, Dalod M, Pace L, Caronni N, Guermonprez P, Benvenuti F

Link to Pubmed [PMID] – 38480738

Link to DOI – 10.1038/s41467-024-46685-y

Nat Commun 2024 Mar; 15(1): 2280

Cross-presentation by type 1 DCs (cDC1) is critical to induce and sustain antitumoral CD8 T cell responses to model antigens, in various tumor settings. However, the impact of cross-presenting cDC1 and the potential of DC-based therapies in tumors carrying varied levels of bona-fide neoantigens (neoAgs) remain unclear. Here we develop a hypermutated model of non-small cell lung cancer in female mice, encoding genuine MHC-I neoepitopes to study neoAgs-specific CD8 T cell responses in spontaneous settings and upon Flt3L + αCD40 (DC-therapy). We find that cDC1 are required to generate broad CD8 responses against a range of diverse neoAgs. DC-therapy promotes immunogenicity of weaker neoAgs and strongly inhibits the growth of high tumor-mutational burden (TMB) tumors. In contrast, low TMB tumors respond poorly to DC-therapy, generating mild CD8 T cell responses that are not sufficient to block progression. scRNA transcriptional analysis, immune profiling and functional assays unveil the changes induced by DC-therapy in lung tissues, which comprise accumulation of cDC1 with increased immunostimulatory properties and less exhausted effector CD8 T cells. We conclude that boosting cDC1 activity is critical to broaden the diversity of anti-tumoral CD8 T cell responses and to leverage neoAgs content for therapeutic advantage.