López et al. investigated the impact of cross-presenting type 1 dendritic cells (cDC1), with or without DC therapy (Flt3L + anti-CD40), in a mouse lung tumor model with a defined pattern of endogenous neoantigens (neoAgs) and a high or low tumor mutational burden (TMB). cDC1 were critical for enhancing and broadening CD8+ T cell responses to less immunogenic antigens, and were required for the antitumoral effect of DC therapy. DC therapy promoted the immunogenicity of weaker neoAgs, and strongly inhibited high-TMB tumor growth, but not low-TMB growth. DC therapy expanded effector, less exhausted CD8+ T cells, and increased cDC1 in lung tissue.
Contributed by Katherine Turner
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.
Author Info: (1) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (2) Cellular Immunology, International Centre for Genetic Engineerin
Author Info: (1) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (2) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (3) San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy. (4) Universit Paris Cit, Institut Cochin, INSERM 1016, Paris, France. Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, KU Leuven, Leuven, Belgium. (5) Department of Oncology, Molecular Biotechnology Center, University of Torino, Turin, Italy. Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria. (6) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (7) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (8) G. Armenise-Harvard Immune Regulation Unit, IIGM, Candiolo, TO, Italy. Candiolo Cancer Institute, FPO-IRCCS, Candiolo, TO, Italy. (9) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. Cellular and Molecular Oncoimmunology, IRCCS Humanitas Research Hospital, Rozzano, Italy. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy. (10) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (11) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (12) Center for Omics Sciences, IRCCS San Raffaele Institute, Milano, Italy. Vita-Salute San Raffaele University, Milan, Italy. (13) Center for Omics Sciences, IRCCS San Raffaele Institute, Milano, Italy. Vita-Salute San Raffaele University, Milan, Italy. (14) Department of Oncology, Molecular Biotechnology Center, University of Torino, Turin, Italy. IFOM ETS - The AIRC Institute of Molecular Oncology, 20139, Milan, Italy. (15) Department of Dermatology, Venereology & Allergology, Medical University of Innsbruck, Innsbruck, Austria. (16) Department of Oncology, Molecular Biotechnology Center, University of Torino, Turin, Italy. IFOM ETS - The AIRC Institute of Molecular Oncology, 20139, Milan, Italy. (17) Aix-Marseille University, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Turing Center for Living Systems, Marseille, France. (18) G. Armenise-Harvard Immune Regulation Unit, IIGM, Candiolo, TO, Italy. Candiolo Cancer Institute, FPO-IRCCS, Candiolo, TO, Italy. (19) San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy. (20) Institut Pasteur, CNRS 3738, University de Paris Cit, Paris, France. (21) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. benvenut@icgeb.org.
