Department of Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy.
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.
Nat Commun. 2021 Apr 14;12(1):2237. doi: 10.1038/s41467-021-22535-z.
Acquisition of cell-associated tumor antigens by type 1 dendritic cells (cDC1) is essential to induce and sustain tumor specific CD8 T cells via cross-presentation. Here we show that capture and engulfment of cell associated antigens by tissue resident lung cDC1 is inhibited during progression of mouse lung tumors. Mechanistically, loss of phagocytosis is linked to tumor-mediated downregulation of the phosphatidylserine receptor TIM4, that is highly expressed in normal lung resident cDC1. TIM4 receptor blockade and conditional cDC1 deletion impair activation of tumor specific CD8 T cells and promote tumor progression. In human lung adenocarcinomas, TIM4 transcripts increase the prognostic value of a cDC1 signature and predict responses to PD-1 treatment. Thus, TIM4 on lung resident cDC1 contributes to immune surveillance and its expression is suppressed in advanced tumors.
1 型树突状细胞（cDC1）摄取细胞相关肿瘤抗原对于通过交叉呈递诱导和维持肿瘤特异性 CD8 T 细胞至关重要。在这里，我们表明，在小鼠肺肿瘤进展过程中，组织驻留的肺 cDC1 摄取和吞噬细胞相关抗原受到抑制。从机制上讲，吞噬作用的丧失与肿瘤介导的磷酯酰丝氨酸受体 TIM4 下调有关，TIM4 在正常肺驻留 cDC1 中高度表达。TIM4 受体阻断和条件性 cDC1 缺失会损害肿瘤特异性 CD8 T 细胞的激活，并促进肿瘤进展。在人类肺腺癌中，TIM4 转录本增加了 cDC1 特征的预后价值，并预测对 PD-1 治疗的反应。因此，肺驻留 cDC1 上的 TIM4 有助于免疫监视，其在晚期肿瘤中受到抑制。
