PD-1 Signaling Promotes Tumor-Infiltrating Myeloid-Derived Suppressor Cells and Gastric Tumorigenesis in Mice.
PD-1 Signaling Promotes Tumor-Infiltrating Myeloid-Derived Suppressor Cells and Gastric Tumorigenesis in Mice.
复制标题
PD-1信号转导促进小鼠肿瘤浸润骨髓源性抑制细胞和胃肿瘤发生。
DOI：
10.1053/j.gastro.2020.10.036
复制
发表时间：
2021-03
期刊：
影响因子：
29.4
通讯作者：
Wang TC
中科院分区：
文献类型：
--
作者：
Kim W;Chu TH;Nienhüser H;Jiang Z;Del Portillo A;Remotti HE;White RA;Hayakawa Y;Tomita H;Fox JG;Drake CG;Wang TC
免疫检查点抑制剂在许多肿瘤中的疗效有限。我们研究了胃癌小鼠肿瘤对程序性细胞死亡抑制因子1(PDCD1，也称为PD1)的耐药机制及其配体PDL1的作用。胃泌素缺陷小鼠被给予饮用水中的N-甲基-N-亚硝脲(MNU)和猫科幽门螺杆菌诱导胃肿瘤形成；我们还对H/K-ATPase-hIL1B小鼠进行了研究，H/K-ATPase-hIL1B小鼠在胃窦-体部交界处发生自发性胃肿瘤，并具有构成分泌IL1B的壁细胞。在肿瘤形成之前，小鼠被注射了抗PD1的抗体或同型对照，或在肿瘤发生后注射了抗PD1、5-氟尿嘧啶和奥沙利铂，或抗淋巴细胞抗原6复合体G(也称为Gr-1)的抗体(它耗尽了髓系来源的抑制细胞[MDSCs])。我们培育出了在胃上皮或髓系中特异表达PDL1的敲门小鼠。当在肿瘤生长前给予胃泌素缺陷小鼠时，抗PD1显著减小肿瘤大小，并增加T细胞对肿瘤的侵袭。然而，单独的抗PD1对这些小鼠已建立的肿瘤没有显著影响。在有MDSCs存在的H/K-ATPase-hIL1B小鼠中，早期和晚期给予抗PD1都不会减少肿瘤的生长。联合应用5-氟尿嘧啶和奥沙利铂可减少MDSCs，增加肿瘤内CD8+T细胞的数量，并增强肿瘤对抗PD1的应答，但这会导致肿瘤PDL1表达增加。肿瘤细胞或免疫细胞表达PDL1可增加MNU小鼠胃肿瘤的发生。具有表达PDL1的胃上皮细胞的小鼠不会发生自发肿瘤，但在注射MNU和H.Felis后，它们会发展出更多更大的肿瘤，并积累MDSCs。在小鼠胃癌模型中，5-氟尿嘧啶和奥沙利铂可减少MDSCs的数量，从而增强抗PD1的作用，从而促进CD8+T细胞对肿瘤的侵袭。然而，这些化疗药物也可以诱导肿瘤细胞表达PDL1。胃上皮细胞表达PDL1增加了对MNU和H.Felis的致瘤性，并增加了MDSCs的积累，从而促进了肿瘤的进展。因此，PDL1表达的时机和部位在胃肿瘤的发生中是重要的，在设计治疗方案时应予以考虑。
Immune checkpoint inhibitors have limited efficacy in many tumors. We investigated mechanisms of tumor resistance to inhibitors of programmed cell death 1 (PDCD1, also called PD1) in mice with gastric cancer, and the role of its ligand, PDL1. Gastrin-deficient mice were given N-methyl-N-nitrosourea (MNU) in drinking water along with Helicobacter felis to induce gastric tumor formation; we also performed studies with H/K-ATPase-hIL1B mice, which develop spontaneous gastric tumors at the antral-corpus junction and have parietal cells that constitutively secrete IL1B. Mice were given injections of an antibody against PD1 or an isotype control before tumors developed, or anti-PD1 and 5-fluorouracil and oxaliplatin, or an antibody against lymphocyte antigen 6 complex locus G (also called Gr-1), which depletes myeloid-derived suppressor cells [MDSCs]), after tumors developed. We generated knockin mice that express PDL1 specifically in the gastric epithelium or myeloid lineage. When given to gastrin-deficient mice before tumors grew, anti-PD1 significantly reduced tumor size and increased tumor infiltration by T cells. However, anti-PD1 alone did not have significant effects on established tumors in these mice. Neither early nor late anti-PD1 administration reduced tumor growth in the presence of MDSCs in H/K-ATPase-hIL1B mice. The combination of 5-fluorouracil and oxaliplatin reduced MDSCs, increased numbers of intra-tumor CD8+ T cells, and increased the response of tumors to anti-PD1—however, this resulted in increased tumor expression of PDL1. Expression of PDL1 by tumor or immune cells increased gastric tumorigenesis in mice given MNU. Mice with gastric epithelial cells that expressed PDL1 did not develop spontaneous tumors, but they developed more and larger tumors after administration of MNU and H. felis, with accumulation of MDSCs. In mouse models of gastric cancer, 5-fluorouracil and oxaliplatin reduce numbers of MDSCs to increase the effects of anti-PD1, which promotes tumor infiltration by CD8+ T cells. However, these chemotherapeutic agents also induce expression of PDL1 by tumor cells. Expression of PDL1 by gastric epithelial cells increases tumorigenesis in response to MNU and H. felis, and accumulation of MDSCs, which promote tumor progression. The timing and site of PDL1 expression is therefore important in gastric tumorigenesis and should be considered in design of therapeutic regimens.
登录
查看更多内容
影响因子：
16.6
作者：
Dubeykovskaya Z;Si Y;Chen X;Worthley DL;Renz BW;Urbanska AM;Hayakawa Y;Xu T;Westphalen CB;Dubeykovskiy A;Chen D;Friedman RA;Asfaha S;Nagar K;Tailor Y;Muthupalani S;Fox JG;Kitajewski J;Wang TC
通讯作者：
Wang TC
DOI：
10.1084/jem.20160801
发表时间：
2017-04-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Juneja VR;McGuire KA;Manguso RT;LaFleur MW;Collins N;Haining WN;Freeman GJ;Sharpe AH
通讯作者：
Sharpe AH
影响因子：
17.1
作者：
Highfill SL;Cui Y;Giles AJ;Smith JP;Zhang H;Morse E;Kaplan RN;Mackall CL
通讯作者：
Mackall CL
影响因子：
8
作者：
Markowitz, Geoffrey J.;Havel, Lauren S.;Mittal, Vivek
通讯作者：
Mittal, Vivek
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I