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

Differentiation of proinflammatory CD4(+) conventional T cells (T-conv) 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(+) T-conv, but then fail to support antitumor CD4(+) T-conv differentiation. Regulatory T cell (T-reg) depletion enhanced their capacity to elicit strong CD4(+) T-conv responses and ensuing antitumor protection. Analogous cDC2 populations were identified in patients, and as in mice, their abundance relative to T-reg predicts protective ICOS+ PD-1(lo) CD4(+) T-conv phenotypes and survival. Further, in melanoma patients with low T-reg abundance, intratumoral cDC2 density alone correlates with abundant CD4(+) T-conv and with responsiveness to anti-PD-1 therapy. Together, this highlights a pathway that restrains cDC2 and whose reversal enhances CD4(+) T-conv abundance and controls tumor growth.