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Background: Human conventional dendritic cells (cDC) are essential for the anti-tumor immune response. Their immunogenic and tolerogenic states in cancer remain controversial. Our objective was to define the range of DC activation states in vitro and to determine their relevance ex vivo in cancer. Methods: First, in vitro, we activated healthy donor cDC with 16 different stimuli and measured cDC and T cells cytokine and chemokine secretion upon co-culture (n = 130 individual experiments) to define new maturation archetypes. Second, we established the relevance of these archetypes in cancer, ex vivo in human. We performed in depth analysis of cDC infiltrating head and neck cancer (HNSCC) by flow cytometry (n = 22 patients), transcriptomic analysis (n = 6 patients), and cDC-enriched single-cell transcriptomics (ScRNAseq) (n = 10503 cells from 2 patients). Then we performed a merged analysis of cDC from in house and public ScRNAseq datasets (n = 36 tumor samples from HNSCC, Lung, and Breast cancer, and, as comparator, n = 33 blood and juxtatumor samples, n = 19 healthy donor samples, and n = 23 samples from inflammatory diseases). Results: In vitro, we identified two archetypes of cDC activation: (i) PD-L1highICOSLlow cDC that produce large amounts of inflammatory cytokines and chemokines, labeled Secretory cDC; (ii)PD-L1lowICOSLhigh cDC that induce a broad range of Th cytokines, labeled Helper cDC. This functional dichotomy of cDC was mutually exclusive and not receptor specific. In cancer, we identified Secretory cDC, and these cells aligned with mature LAMP3+cDC. Helper cDC were not found ex vivo. Secretory cDC simultaneously expressed stimulatory (CD40, TNFRSF9 (4-1BB)), inhibitory (CD274, CD200, IDO1), and mixed (PVR) checkpoints. Secretory cDC were associated with T cell inflammation in HNSCC, triple-negative breast cancer (TNBC), and melanoma (all p < 1.10-15), with improved overall survival in HNSCC and TNBC (all p < 0.01), and with response to checkpoint blockade in 2 melanoma cohorts (all p < 0.01). Conclusion: We identify and characterize Secretory cDC in several solid cancers. This novel phenotypic and functional dichotomy of human cDC activation states has broad implications for all types of immunotherapies and provides rational for drug combinations. Citation Format: Caroline Hoffmann, Floriane Noël, Maximilien Grandclaudon, Lucile Massenet-Regad, Paula Michea, Philemon Sirven, Lilith Faucheux, Aurore Surun, Olivier Lantz, Mylene Bohec, Jian Ye, Weihua Guo, Juliette Rochefort, Jerzy Klijanienko, Sylvain Baulande, Charlotte Lecerf, Maud Kamal, Christophe Le Tourneau, Maude Guillot-Delost, Vassili Soumelis. PD-L1 high ICOSL low Secretory dendritic cells infiltrate human solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2105. |
