BackgroundHuman papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is a distinct clinical entity with a much better prognosis after (chemo)radiotherapy than HPV-negative OPSCC, especially in patients with a concomitant intratumoral HPV-specific and type-1 cytokine-oriented T cell response. However, knowledge on the type of myeloid cells and their coordination with intratumoral T cells and influence on patient outcome in OPSCC is lacking.MethodsWe analyzed the presence of intratumoral myeloid cells and their relationship to tumor-infiltrating T cells and patient outcome in a well-described cohort of HPV16⁺ patients with OPSCC using multispectral immunofluorescence, flow cytometry and functional analyses.ResultsWe show that the tumor microenvironment of HPV16⁺ OPSCC tumors with such an ongoing HPV16-specific T cell response is highly infiltrated with a newly defined CD163⁺ cytokine-producing subset of conventional dendritic cell type 2 (cDC2), called DC3. These CD163⁺ cDC2 predominantly stimulated type 1 T cell polarization and produced high levels of interleukin-12 (IL-12) and IL-18, required for IFNγ and IL-22 production by T cells after cognate antigen stimulation. Tumor-infiltration with these CD163⁺ cDC2 positively correlated with the infiltration by Tbet⁺ and tumor-specific T cells, and with prolonged survival.ConclusionsThese data suggest an important role for intratumoral CD163⁺ cDC2 in stimulating tumor-infiltrating T cells to exert their antitumor effects.