Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego (UCSD), La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, CA, USA; Cellular and Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, WI, USA.
Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego (UCSD), La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, CA, USA.
Cell Rep. 2022 Aug 16;40(7):111201. doi: 10.1016/j.celrep.2022.111201.
Stimulatory type 1 conventional dendritic cells (cDC1s) engage in productive interactions with CD8 effectors along tumor-stroma boundaries. The paradoxical accumulation of "poised" cDC1s within stromal sheets is unlikely to simply reflect passive exclusion from tumor cores. Drawing parallels with embryonic morphogenesis, we hypothesized that invasive margin stromal remodeling generates developmentally conserved cell fate cues that regulate cDC1 behavior. We find that, in human T cell-inflamed tumors, CD8 T cells penetrate tumor nests, whereas cDC1s are confined within adjacent stroma that recurrently displays site-specific proteolysis of the matrix proteoglycan versican (VCAN), an essential organ-sculpting modification in development. VCAN is necessary, and its proteolytic fragment (matrikine) versikine is sufficient for cDC1 accumulation. Versikine does not influence tumor-seeding pre-DC differentiation; rather, it orchestrates a distinctive cDC1 activation program conferring exquisite sensitivity to DNA sensing, supported by atypical innate lymphoid cells. Thus, peritumoral stroma mimicking embryonic provisional matrix remodeling regulates cDC1 abundance and activity to elicit T cell-inflamed tumor microenvironments.
刺激型 1 传统树突状细胞 (cDC1) 与 CD8 效应细胞沿着肿瘤-基质边界进行有效相互作用。在基质片中堆积“准备好”的 cDC1 的矛盾现象不太可能仅仅反映出它们被被动排除在肿瘤核心之外。与胚胎形态发生相类比，我们假设侵袭性边缘基质重塑产生了调节 cDC1 行为的发育保守的细胞命运线索。我们发现，在人类 T 细胞浸润的肿瘤中，CD8 T 细胞穿透肿瘤巢，而 cDC1 则局限于相邻的基质中，基质中反复出现基质蛋白聚糖 versican（VCAN）的特异性蛋白水解，VCAN 是发育过程中必不可少的器官塑造修饰。VCAN 是必需的，其蛋白水解片段（基质素）versikine 足以引起 cDC1 的积累。Versikine 不影响肿瘤播种前 DC 的分化；相反，它协调了一个独特的 cDC1 激活程序，赋予对 DNA 感应的极高敏感性，由非典型先天淋巴细胞支持。因此，模拟胚胎临时基质重塑的肿瘤周围基质调节 cDC1 的丰度和活性，引发 T 细胞浸润的肿瘤微环境。
