The interaction of CD4+ helper T cells with dendritic cells shapes the tumor microenvironment and immune checkpoint blockade response
Cohen, Merav; Giladi, Amir; Barboy, Oren; Hamon, Pauline; Li, Baoguo; Zada, Mor; Gurevich-Shapiro, Anna; Beccaria, Cristian Gabriel; David, Eyal; Maier, Barbara B.; Buckup, Mark; Kamer, Iris; Deczkowska, Aleksandra; Le Berichel, Jessica; Bar, Jair; Iannacone, Matteo; Tanay, Amos; Merad, Miriam; Amit, Ido
(2022) Nature Cancer, volume 3, issue 3, pp. 303 - 317
(Article)
Abstract
Despite their key regulatory role and therapeutic potency, the molecular signatures of interactions between T cells and antigen-presenting myeloid cells within the tumor microenvironment remain poorly characterized. Here, we systematically characterize these interactions using RNA sequencing of physically interacting cells (PIC-seq) and find that CD4+PD-1+CXCL13+ T cells are a major
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interacting hub with antigen-presenting cells in the tumor microenvironment of human non-small cell lung carcinoma. We define this clonally expanded, tumor-specific and conserved T-cell subset as T-helper tumor (Tht) cells. Reconstitution of Tht cells in vitro and in an ovalbumin-specific αβ TCR CD4+ T-cell mouse model, shows that the Tht program is primed in tumor-draining lymph nodes by dendritic cells presenting tumor antigens, and that their function is important for harnessing the antitumor response of anti-PD-1 treatment. Our molecular and functional findings support the modulation of Tht–dendritic cell interaction checkpoints as a major interventional strategy in immunotherapy.
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Keywords: Animals, Cell Line, Tumor, Dendritic Cells, Immune Checkpoint Inhibitors/pharmacology, Lung Neoplasms/therapy, Mice, T-Lymphocytes, Helper-Inducer, Tumor Microenvironment, General Medicine, Oncology, Cancer Research, Research Support, Non-U.S. Gov't, Journal Article, Research Support, N.I.H., Extramural
ISSN: 2662-1347
Publisher: Nature Research
Note: Funding Information: We thank T. Wiesel for artwork and the Dean?s Flow Cytometry CORE and Biorepository and Pathology CoRE Laboratory of the Icahn School of Medicine at Mount Sinai. The research of I.A. and A.T. is supported by the Seed Networks for the Human Cell Atlas of the Chan Zuckerberg Initiative and by Merck KGaA, Darmstadt. I.A. is an Eden and Steven Romick Professorial Chair, supported by the HHMI International Scholar Award, the European Research Council Consolidator grant (no. 724471-HemTree2.0), an MRA Established Investigator award (no. 509044), DFG (no. SFB/TRR167), the Ernest and Bonnie Beutler Research Program for Excellence in Genomic Medicine, the Helen and Martin Kimmel awards for innovative investigation and the SCA award of the Wolfson Foundation and Family Charitable Trust. The Thompson Family Foundation Alzheimer?s Research Fund and the Adelis Foundation also provided support. The laboratory of A.T. is supported by the European Research Council (no. 724824), the I-CORE for chromatin and RNA regulation, a grant from the Israel Science Foundation and a grant from the Kahn Foundation. A.T. is a Kimmel investigator. The laboratory of M.M. is supported by R01 CA257195, R01 CA254104 and Samuel Waxman Cancer Research Foundation. A.G. is funded by the Rothschild Postdoctoral Fellowship of the Yad Hanadiv Foundation. Funding Information: We thank T. Wiesel for artwork and the Dean’s Flow Cytometry CORE and Biorepository and Pathology CoRE Laboratory of the Icahn School of Medicine at Mount Sinai. The research of I.A. and A.T. is supported by the Seed Networks for the Human Cell Atlas of the Chan Zuckerberg Initiative and by Merck KGaA, Darmstadt. I.A. is an Eden and Steven Romick Professorial Chair, supported by the HHMI International Scholar Award, the European Research Council Consolidator grant (no. 724471-HemTree2.0), an MRA Established Investigator award (no. 509044), DFG (no. SFB/TRR167), the Ernest and Bonnie Beutler Research Program for Excellence in Genomic Medicine, the Helen and Martin Kimmel awards for innovative investigation and the SCA award of the Wolfson Foundation and Family Charitable Trust. The Thompson Family Foundation Alzheimer’s Research Fund and the Adelis Foundation also provided support. The laboratory of A.T. is supported by the European Research Council (no. 724824), the I-CORE for chromatin and RNA regulation, a grant from the Israel Science Foundation and a grant from the Kahn Foundation. A.T. is a Kimmel investigator. The laboratory of M.M. is supported by R01 CA257195, R01 CA254104 and Samuel Waxman Cancer Research Foundation. A.G. is funded by the Rothschild Postdoctoral Fellowship of the Yad Hanadiv Foundation. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
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