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PD-1 Signaling Promotes Tumor-Infiltrating Myeloid-Derived Suppressor Cells and Gastric Tumorigenesis in Mice
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nihms-1643810.pdf
Description
Accepted version
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3.05 MB
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Checksum (MD5)
ea69c50bd05bf307c4928e5415d7f98e
Author(s)
Kim, Woosook
Chu, Timothy H
Nienhüser, Henrik
Jiang, Zhengyu
Del Portillo, Armando
Remotti, Helen E
White, Ruth A
Hayakawa, Yoku
Tomita, Hiroyuki
Fox, James G
Date Issued
2021
Journal
Gastroenterology
Publisher
Elsevier BV
Citation
Kim, Woosook, Chu, Timothy H, Nienhüser, Henrik, Jiang, Zhengyu, Del Portillo, Armando et al. 2021. "PD-1 Signaling Promotes Tumor-Infiltrating Myeloid-Derived Suppressor Cells and Gastric Tumorigenesis in Mice." Gastroenterology, 160 (3).
Version
Author's final manuscript
Abstract
© 2021 AGA Institute Background & Aims: 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 PD-1) in mice with gastric cancer, and the role of its ligand, PD-L1. Methods: 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 interleukin 1B. Mice were given injections of an antibody against PD-1 or an isotype control before tumors developed, or anti–PD-1 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 knock-in mice that express PD-L1 specifically in the gastric epithelium or myeloid lineage. Results: When given to gastrin-deficient mice before tumors grew, anti–PD-1 significantly reduced tumor size and increased tumor infiltration by T cells. However, anti–PD-1 alone did not have significant effects on established tumors in these mice. Neither early nor late anti–PD-1 administration reduced tumor growth in the presence of MDSCs in H/K-ATPase-hIL-1β 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–PD-1; however, this resulted in increased tumor expression of PD-L1. Expression of PD-L1 by tumor or immune cells increased gastric tumorigenesis in mice given MNU. Mice with gastric epithelial cells that expressed PD-L1 did not develop spontaneous tumors, but they developed more and larger tumors after administration of MNU and H felis, with accumulation of MDSCs. Conclusions: In mouse models of gastric cancer, 5-fluorouracil and oxaliplatin reduce numbers of MDSCs to increase the effects of anti–PD-1, which promotes tumor infiltration by CD8+ T cells. However, these chemotherapeutic agents also induce expression of PD-L1 by tumor cells. Expression of PD-L1 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 PD-L1 expression is therefore important in gastric tumorigenesis and should be considered in design of therapeutic regimens.
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DOI of Published Version
10.1053/J.GASTRO.2020.10.036
