OX40+ plasmacytoid dendritic cells in the tumor microenvironment promote antitumor immunity
Kate Poropatich, Donye Dominguez, Wen-Ching Chan, Jorge Andrade, Yuanyuan Zha, Brian Wray, Jason Miska, Lei Qin, Lisa Cole, Sydney Coates, Urjeet Patel, Sandeep Samant, Bin Zhang
Kate Poropatich, Donye Dominguez, Wen-Ching Chan, Jorge Andrade, Yuanyuan Zha, Brian Wray, Jason Miska, Lei Qin, Lisa Cole, Sydney Coates, Urjeet Patel, Sandeep Samant, Bin Zhang
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Research Article Immunology Oncology

OX40+ plasmacytoid dendritic cells in the tumor microenvironment promote antitumor immunity

Abstract

Plasmacytoid DCs (pDCs), the major producers of type I interferon, are principally recognized as key mediators of antiviral immunity. However, their role in tumor immunity is less clear. Depending on the context, pDCs can promote or suppress antitumor immune responses. In this study, we identified a naturally occurring pDC subset expressing high levels of OX40 (OX40+ pDC) enriched in the tumor microenvironment (TME) of head and neck squamous cell carcinoma. OX40+ pDCs were distinguished by a distinct immunostimulatory phenotype, cytolytic function, and ability to synergize with conventional DCs (cDCs) in generating potent tumor antigen–specific CD8+ T cell responses. Transcriptomically, we found that they selectively utilized EIF2 signaling and oxidative phosphorylation pathways. Moreover, depletion of pDCs in the murine OX40+ pDC–rich tumor model accelerated tumor growth. Collectively, we present evidence of a pDC subset in the TME that favors antitumor immunity.

Authors

Kate Poropatich, Donye Dominguez, Wen-Ching Chan, Jorge Andrade, Yuanyuan Zha, Brian Wray, Jason Miska, Lei Qin, Lisa Cole, Sydney Coates, Urjeet Patel, Sandeep Samant, Bin Zhang

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Figure 2

OX40+ pDCs have a distinct immunostimulatory phenotype.

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OX40+ pDCs have a distinct immunostimulatory phenotype. (A) After overni...
(A) After overnight incubation, pDCs from the dLNs– of HNSCC patients (n = 7) were harvested and measured by flow cytometry for expression of different surface markers. Single gradient mean values are shown. (B) Representative histograms of OX40+ and OX40lo/– pDC surface marker expression. (C) Expression of IL-12p70+CD86+ populations on sorted cDCs and pDCs, either unstimulated (controls; bottom) or in the presence of Resiquimod (top). n = 2; 2 experimental patient repeats. (D) Percentages (by flow cytometry) of dLN– pDCs positive for TRAIL (n = 5) and GzB (n = 4) after overnight stimulation with CpG or Resiquimod. (E) The concentration (pg/mL) of IFN-α (n = 10) and TRAIL (n = 6) in the supernatant from sorted OX40+ and OX40lo/– pDCs from the TME and non-TME stimulated with either CpG or Resiquimod. Data normalized to 2 × 103 pDCs per sample. (F) May-Grunwald staining of OX40+ and OX40lo/– pDC subsets stimulated with Resiquimod. Scale bar: 5 μm. n = 4, 4 experimental patient repeats. Two-way ANOVA with Sidak’s test for multiple comparisons (A). Two-tailed paired t test (D and E). *P < 0.05. Bar graph data are mean ± SEM; middle line of box-and-whisker plot indicates the median, box limits indicate the first and third quartiles, and whiskers indicate “extreme” for all data points.