Targeting myeloid suppressive cells revives cytotoxic anti-tumor responses in pancreatic cancer.
Targeting myeloid suppressive cells revives cytotoxic anti-tumor responses in pancreatic cancer.
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DOI：
10.1016/j.isci.2022.105317
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发表时间：
2022-11-18
期刊：
影响因子：
5.8
通讯作者：
Karlsson, Mikael C., I
中科院分区：
文献类型：
--
作者：
Sarhan, Dhifaf;Eisinger, Silke;He, Fei;Bergsland, Maria;Pelicano, Catarina;Driescher, Caroline;Westberg, Kajsa;Benitez, Itziar Ibarlucea;Humoud, Rawan;Palano, Giorgia;Li, Shuijie;Carannante, Valentina;Muhr, Jonas;Onfelt, Bjorn;Schlisio, Susanne;Ravetch, Jeffrey, V;Heuchel, Rainer;Lohr, Matthias J.;Karlsson, Mikael C., I
旨在促进T细胞抗肿瘤活性的癌症免疫疗法已经改变了当前的临床实践，其中一些以前致命的癌症现在已经变得可以治疗。然而，针对胰腺导管腺癌（PDAC）的临床试验反应率较低，令人失望。一种建议的解释是在肿瘤微环境（TME）中积累了占主导地位的免疫抑制性肿瘤相关巨噬细胞和髓源性抑制细胞。使用回顾性收集的肿瘤标本和PDAC的转录组数据，我们证明清道夫受体MARCO的表达与预后不良和淋巴细胞排除肿瘤表型相关。PDAC细胞系产生IL-10并诱导骨髓细胞中MARCO的高表达，并且这在缺氧条件下进一步增强。在PDAC 3D球体模型中，这些骨髓细胞抑制效应T和自然杀伤（NK）细胞，并阻断NK细胞肿瘤浸润和肿瘤杀伤。抗人MARCO（抗hMARCO）抗体靶向触发了肿瘤相关巨噬细胞的复极化，并激活了炎性小体机制，导致IL-18产生。这反过来又增强了T细胞和NK细胞的功能。因此，MARCO的靶向重塑了TME，并代表了一种合理的方法，使PDAC患者的免疫治疗更有效。胰腺肿瘤驱动骨髓细胞的免疫抑制表型抗体激活表达MARCO的骨髓细胞以释放细胞毒性细胞MARCO的表达与人类胰腺癌生存率降低有关免疫学;免疫系统的组成部分;癌症
Immunotherapy for cancer that aims to promote T cell anti-tumor activity has changed current clinical practice, where some previously lethal cancers have now become treatable. However, clinical trials with low response rates have been disappointing for pancreatic ductal adenocarcinoma (PDAC). One suggested explanation is the accumulation of dominantly immunosuppressive tumor-associated macrophages and myeloid-derived suppressor cells in the tumor microenvironment (TME). Using retrospectively collected tumor specimens and transcriptomic data from PDAC, we demonstrate that expression of the scavenger receptor MARCO correlates with poor prognosis and a lymphocyte-excluding tumor phenotype. PDAC cell lines produce IL-10 and induce high expression of MARCO in myeloid cells, and this was further enhanced during hypoxic conditions. These myeloid cells suppressed effector T and natural killer (NK) cells and blocked NK cell tumor infiltration and tumor killing in a PDAC 3D-spheroid model. Anti-human MARCO (anti-hMARCO) antibody targeting triggered the repolarization of tumor-associated macrophages and activated the inflammasome machinery, resulting in IL-18 production. This in turn enhanced T cell and NK cell functions. The targeting of MARCO thus remodels the TME and represents a rational approach to make immunotherapy more efficient in PDAC patients. Pancreatic tumors drive an immunosuppressive phenotype of myeloid cells Antibodies activate MARCO-expressing myeloid cells to release cytotoxic cells Expression of MARCO is connected to decreasing survival in human pancreatic cancer Immunology; Components of the immune system; Cancer
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
8.8
作者：
Ino Y;Yamazaki-Itoh R;Shimada K;Iwasaki M;Kosuge T;Kanai Y;Hiraoka N
通讯作者：
Hiraoka N
DOI：
10.2147/dddt.s80888
发表时间：
2015
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Erickson LA;Highsmith WE Jr;Fei P;Zhang J
通讯作者：
Zhang J
影响因子：
11.2
作者：
Chang, Qing;Jurisica, Igor;Hedley, David W.
通讯作者：
Hedley, David W.
影响因子：
29.4
作者：
Ene-Obong A;Clear AJ;Watt J;Wang J;Fatah R;Riches JC;Marshall JF;Chin-Aleong J;Chelala C;Gribben JG;Ramsay AG;Kocher HM
通讯作者：
Kocher HM