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

Author

Listed:
  • 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
    VIB)

  • Giuseppe Rospo

    (University of Torino
    Boehringer Ingelheim RCV GmbH & Co KG)

  • Roberto Amadio

    (International Centre for Genetic Engineering and Biotechnology)

  • Giulia Maria Piperno

    (International Centre for Genetic Engineering and Biotechnology)

  • Valentina Russo

    (IIGM
    FPO-IRCCS)

  • Camilla Volponi

    (International Centre for Genetic Engineering and Biotechnology
    IRCCS Humanitas Research Hospital
    Humanitas University)

  • Simone Vodret

    (International Centre for Genetic Engineering and Biotechnology)

  • Sonal Joshi

    (International Centre for Genetic Engineering and Biotechnology)

  • Francesca Giannese

    (IRCCS San Raffaele Institute
    Vita-Salute San Raffaele University)

  • Dejan Lazarevic

    (IRCCS San Raffaele Institute
    Vita-Salute San Raffaele University)

  • Giovanni Germano

    (University of Torino
    IFOM ETS - The AIRC Institute of Molecular Oncology)

  • Patrizia Stoitzner

    (Medical University of Innsbruck)

  • Alberto Bardelli

    (University of Torino
    IFOM ETS - The AIRC Institute of Molecular Oncology)

  • Marc Dalod

    (Turing Center for Living Systems)

  • Luigia Pace

    (IIGM
    FPO-IRCCS)

  • Nicoletta Caronni

    (IRCCS San Raffaele Scientific Institute)

  • Pierre Guermonprez

    (CNRS 3738, University de Paris Cité)

  • Federica Benvenuti

    (International Centre for Genetic Engineering and Biotechnology)

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.

Suggested Citation

  • Lucía López & Luciano Gastón Morosi & Federica Terza & Pierre Bourdely & Giuseppe Rospo & Roberto Amadio & Giulia Maria Piperno & Valentina Russo & Camilla Volponi & Simone Vodret & Sonal Joshi & Fran, 2024. "Dendritic cell-targeted therapy expands CD8 T cell responses to bona-fide neoantigens in lung tumors," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46685-y
    DOI: 10.1038/s41467-024-46685-y
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