DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells.
DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells.
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DOI：
10.1136/jitc-2020-002054
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发表时间：
2021-05
影响因子：
10.9
通讯作者：
Sancho D
中科院分区：
文献类型：
--
作者：
Cueto FJ;Del Fresno C;Brandi P;Combes AJ;Hernández-García E;Sánchez-Paulete AR;Enamorado M;Bromley CP;Gomez MJ;Conde-Garrosa R;Mañes S;Zelenay S;Melero I;Iborra S;Krummel MF;Sancho D
传统的1型树突状细胞（cDC 1）是抗肿瘤免疫的核心，它们在肿瘤微环境中的存在与癌症患者的预后改善有关。DNGR-1（CLEC 9A）是一种死亡细胞感应受体，高度局限于cDC 1。DNGR-1参与了死亡细胞相关抗原的交叉呈递和疾病耐受过程，但其在抗肿瘤免疫中的作用尚未阐明。将B16和MC 38肿瘤细胞系皮下接种到野生型（WT）和DNGR-1缺陷型小鼠中。为了过表达Flt 3L系统，我们通过流体动力学注射Flt 3L编码质粒进行基因治疗。为了表征免疫应答，我们对肿瘤浸润性cDC 1进行了流式细胞术和RNA-Seq。在这里，我们发现在稳态下肿瘤抗原的交叉呈递是不依赖于DNGR-1的。然而，在Flt 3L系统性过表达时，与WT小鼠相比，DNGR-1缺陷小鼠的肿瘤生长延迟。值得注意的是，这种保护作用在Flt 3L基因治疗后的小鼠中被抗DNGR-1阻断抗体重演。这种改善的抗肿瘤免疫力与Batf 3依赖性增强的CD 8 + T细胞和cDC 1在肿瘤内的积累有关。从机制上讲，DNGR-1的缺乏增强了cDC 1中Flt 3L诱导的特异性炎症基因特征，包括Ccl 5的表达。事实上，cDC 1在肿瘤内的浸润增加及其保护作用依赖于CCL 5/CCR 5的化学吸引。此外，FLT 3LG和CCL 5或CCR 5基因表达特征与增强的cDC 1特征和癌症患者的有利总生存期相关。值得注意的是，环磷酰胺升高了血清Flt 3L水平，并且与不存在DNGR-1相结合，协同对抗肿瘤生长。DNGR-1限制了Flt 3L促进的肿瘤浸润性cDC 1的积累。因此，DNGR-1阻断可改善与高Flt 3L表达相关的肿瘤治疗环境中的抗肿瘤免疫。
Conventional type 1 dendritic cells (cDC1s) are central to antitumor immunity and their presence in the tumor microenvironment associates with improved outcomes in patients with cancer. DNGR-1 (CLEC9A) is a dead cell-sensing receptor highly restricted to cDC1s. DNGR-1 has been involved in both cross-presentation of dead cell-associated antigens and processes of disease tolerance, but its role in antitumor immunity has not been clarified yet. B16 and MC38 tumor cell lines were inoculated subcutaneously into wild-type (WT) and DNGR-1-deficient mice. To overexpress Flt3L systemically, we performed gene therapy through the hydrodynamic injection of an Flt3L-encoding plasmid. To characterize the immune response, we performed flow cytometry and RNA-Seq of tumor-infiltrating cDC1s. Here, we found that cross-presentation of tumor antigens in the steady state was DNGR-1-independent. However, on Flt3L systemic overexpression, tumor growth was delayed in DNGR-1-deficient mice compared with WT mice. Of note, this protection was recapitulated by anti-DNGR-1-blocking antibodies in mice following Flt3L gene therapy. This improved antitumor immunity was associated with Batf3-dependent enhanced accumulation of CD8+ T cells and cDC1s within tumors. Mechanistically, the deficiency in DNGR-1 boosted an Flt3L-induced specific inflammatory gene signature in cDC1s, including Ccl5 expression. Indeed, the increased infiltration of cDC1s within tumors and their protective effect rely on CCL5/CCR5 chemoattraction. Moreover, FLT3LG and CCL5 or CCR5 gene expression signatures correlate with an enhanced cDC1 signature and a favorable overall survival in patients with cancer. Notably, cyclophosphamide elevated serum Flt3L levels and, in combination with the absence of DNGR-1, synergized against tumor growth. DNGR-1 limits the accumulation of tumor-infiltrating cDC1s promoted by Flt3L. Thus, DNGR-1 blockade may improve antitumor immunity in tumor therapy settings associated to high Flt3L expression.
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FLT3配体处理的小鼠功能成熟的树突状细胞数量的急剧增加：确定的多个树突状细胞亚群。
影响因子：
15.3
作者：
Maraskovsky, E;Brasel, K;Teepe, M;Roux, ER;Lyman, SD;Shortman, K;McKenna, HJ
通讯作者：
McKenna, HJ
DOI：
10.1084/jem.20131397
发表时间：
2014-08-25
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Anandasabapathy N;Feder R;Mollah S;Tse SW;Longhi MP;Mehandru S;Matos I;Cheong C;Ruane D;Brane L;Teixeira A;Dobrin J;Mizenina O;Park CG;Meredith M;Clausen BE;Nussenzweig MC;Steinman RM
通讯作者：
Steinman RM
DOI：
10.1084/jem.20170229
发表时间：
2017-08-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Alloatti A;Rookhuizen DC;Joannas L;Carpier JM;Iborra S;Magalhaes JG;Yatim N;Kozik P;Sancho D;Albert ML;Amigorena S
通讯作者：
Amigorena S
影响因子：
32.4
作者：
Iborra, Salvador;Martinez-Lopez, Maria;Khouili, Sofia C.;Enamorado, Michel;Cueto, Francisco J.;Conde-Garrosa, Ruth;del Fresno, Carlos;Sancho, David
通讯作者：
Sancho, David
影响因子：
32.4
作者：
Iborra, Salvador;Martinez-Lopez, Maria;Cueto, Francisco J.;Conde-Garrosa, Ruth;Del Fresno, Carlos;Izquierdo, Helena M.;Abram, Clare L.;Mori, Daiki;Campos-Martin, Yolanda;Maria Reguera, Rosa;Kemp, Benjamin;Yamasaki, Sho;Robinson, Matthew J.;Soto, Manuel;Lowell, Clifford A.;Sancho, David
通讯作者：
Sancho, David