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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Differentiation
  • Cell Line, Tumor
  • Cytokines / metabolism
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Diphtheria Toxin / immunology
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Lectins, C-Type / genetics
  • Lectins, C-Type / metabolism
  • Lymph Nodes / immunology
  • Lymph Nodes / metabolism
  • Lymphocyte Activation
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Chemokine / metabolism
  • T-Lymphocytes, Regulatory / immunology
  • Tumor Microenvironment

Substances

  • Antigens, Neoplasm
  • Cytokines
  • Diphtheria Toxin
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Lectins, C-Type
  • MGL2 protein, mouse
  • Receptors, Chemokine
  • XC chemokine receptor 1, mouse