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

Lucía López, Luciano Gastón Morosi, Federica Terza, Pierre Bourdely, Giuseppe Rospo, Roberto Amadio, Giulia Maria Piperno, Valentina Russo, Camilla Volponi, Simone Vodret, Sonal Joshi, Francesca Giannese, Dejan Lazarevic, Giovanni Germano, Patrizia Stoitzner, Alberto Bardelli, Marc Dalod, Luigia Pace, Nicoletta Caronni, Pierre Guermonprez and Federica Benvenuti ()
Additional contact information
Lucía López: International Centre for Genetic Engineering and Biotechnology
Luciano Gastón Morosi: International Centre for Genetic Engineering and Biotechnology
Federica Terza: IRCCS San Raffaele Scientific Institute
Pierre Bourdely: INSERM 1016
Giuseppe Rospo: University of Torino
Roberto Amadio: International Centre for Genetic Engineering and Biotechnology
Giulia Maria Piperno: International Centre for Genetic Engineering and Biotechnology
Valentina Russo: IIGM
Camilla Volponi: International Centre for Genetic Engineering and Biotechnology
Simone Vodret: International Centre for Genetic Engineering and Biotechnology
Sonal Joshi: International Centre for Genetic Engineering and Biotechnology
Francesca Giannese: IRCCS San Raffaele Institute
Dejan Lazarevic: IRCCS San Raffaele Institute
Giovanni Germano: University of Torino
Patrizia Stoitzner: Medical University of Innsbruck
Alberto Bardelli: University of Torino
Marc Dalod: Turing Center for Living Systems
Luigia Pace: IIGM
Nicoletta Caronni: IRCCS San Raffaele Scientific Institute
Pierre Guermonprez: CNRS 3738, University de Paris Cité
Federica Benvenuti: International Centre for Genetic Engineering and Biotechnology

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-46685-y

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