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Cell. 2019 Apr 18;177(3):556-571.e16. doi: 10.1016/j.cell.2019.02.005. Epub 2019 Apr 4.

Unleashing Type-2 Dendritic Cells to Drive Protective Antitumor CD4+ T Cell Immunity.

Author information

1
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
2
Pionyr Immunotherapeutics, San Francisco, CA 94080, USA.
3
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF Immunoprofiler Initiative, University of California, San Francisco, San Francisco, CA 94143, USA.
4
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
5
Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
6
Institute of Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA.
7
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF Immunoprofiler Initiative, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: matthew.krummel@ucsf.edu.

Abstract

Differentiation of proinflammatory CD4+ conventional T cells (Tconv) is critical for productive antitumor responses yet their elicitation remains poorly understood. We comprehensively characterized myeloid cells in tumor draining lymph nodes (tdLN) of mice and identified two subsets of conventional type-2 dendritic cells (cDC2) that traffic from tumor to tdLN and present tumor-derived antigens to CD4+ Tconv, but then fail to support antitumor CD4+ Tconv differentiation. Regulatory T cell (Treg) depletion enhanced their capacity to elicit strong CD4+ Tconv responses and ensuing antitumor protection. Analogous cDC2 populations were identified in patients, and as in mice, their abundance relative to Treg predicts protective ICOS+ PD-1lo CD4+ Tconv phenotypes and survival. Further, in melanoma patients with low Treg abundance, intratumoral cDC2 density alone correlates with abundant CD4+ Tconv and with responsiveness to anti-PD-1 therapy. Together, this highlights a pathway that restrains cDC2 and whose reversal enhances CD4+ Tconv abundance and controls tumor growth.

KEYWORDS:

CD4(+) T cells; T cell priming; checkpoint blockade; dendritic cells; immunotherapy; regulatory T cells; tumor immunology; tumor microenvironment

PMID:
30955881
DOI:
10.1016/j.cell.2019.02.005

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