Unleashing Type-2 Dendritic Cells to Drive Protective Antitumor CD4+ T Cell Immunity
Unleashing Type-2 Dendritic Cells to Drive Protective Antitumor CD4+ T Cell Immunity
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DOI：
10.1016/j.cell.2019.02.005
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发表时间：
2019-04-18
期刊：
影响因子：
64.5
通讯作者：
Krummel, Matthew F.
中科院分区：
文献类型：
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作者：
Binnewies, Mikhail;Mujal, Adriana M.;Krummel, Matthew F.
促炎性CD 4（+）常规T细胞（T-conv）的分化对于产生抗肿瘤反应至关重要，但其诱导仍然知之甚少。我们对小鼠肿瘤引流淋巴结（tdLN）中的髓样细胞进行了全面的表征，并鉴定了两种常规2型树突状细胞（cDC 2）亚群，它们从肿瘤运输到tdLN，并将肿瘤衍生抗原呈递给CD 4（+）T-conv，但随后无法支持抗肿瘤CD 4（+）T-conv分化。调节性T细胞（T-reg）耗竭增强了它们引发强烈的CD 4（+）T-conv应答和随后的抗肿瘤保护的能力。在患者中鉴定了类似的cDC 2群体，并且如在小鼠中一样，其相对于T-reg的丰度预测保护性ICOS+ PD-1（lo）CD 4（+）T-conv表型和存活。此外，在T-reg丰度低的黑色素瘤患者中，肿瘤内cDC 2密度单独与丰富的CD 4（+）T-conv和对抗PD-1治疗的反应性相关。总之，这突出了抑制cDC 2的途径，其逆转增强CD 4（+）T-conv丰度并控制肿瘤生长。
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.