Article Dans Une Revue Nature Communications Année : 2024

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

Camilla Volponi
  • Fonction : Auteur
Simone Vodret
  • Fonction : Auteur
Sonal Joshi
  • Fonction : Auteur
Francesca Giannese
Dejan Lazarevic
  • Fonction : Auteur
Giovanni Germano
  • Fonction : Auteur
Marc Dalod
Luigia Pace
  • Fonction : Auteur
Nicoletta Caronni

Résumé

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.
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hal-04583076 , version 1 (22-05-2024)

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Lucía López, Luciano Gastón Morosi, Federica La Terza, Pierre Bourdely, Giuseppe Rospo, et al.. Dendritic cell-targeted therapy expands CD8 T cell responses to bona-fide neoantigens in lung tumors. Nature Communications, 2024, 15 (1), pp.2280. ⟨10.1038/s41467-024-46685-y⟩. ⟨hal-04583076⟩
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