PD-1 Signaling Promotes Tumor-Infiltrating Myeloid-Derived Suppressor Cells and Gastric Tumorigenesis in Mice

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 160; no. 3; pp. 781 - 796
• Main Authors: 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., Drake, Charles G., Wang, Timothy C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2021
• Subjects: Administration, Oral; Animals; Carcinogenesis - chemically induced; Carcinogenesis - drug effects; Carcinogenesis - genetics; Carcinogenesis - immunology; Gastric Mucosa - immunology; Gastric Mucosa - microbiology; Gastric Mucosa - pathology; Gastrins - genetics; Helicobacter felis - immunology; Helicobacter Infections - chemically induced; Helicobacter Infections - genetics; Helicobacter Infections - immunology; Helicobacter Infections - microbiology; Humans; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunosuppression; Methylnitrosourea - administration & dosage; Mice; Mice, Knockout; Mouse Model; Myeloid-Derived Suppressor Cells - immunology; Neoplasms, Experimental - chemically induced; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - immunology; Neoplasms, Experimental - microbiology; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - metabolism; Resistance; Signal Transduction - drug effects; Signal Transduction - immunology; Stomach Cancer; Stomach Neoplasms - chemically induced; Stomach Neoplasms - drug therapy; Stomach Neoplasms - immunology; Stomach Neoplasms - microbiology; Tumor Microenvironment - immunology; Stomach Cancer; IL; MDSC; ICB; GzB; Resistance; IFN; PMN; Immunosuppression; MNU; PD-L; GAS-KO; GC; PD-1; Hf; Mouse Model; 5-FU
• ISSN: 0016-5085; 1528-0012; 1528-0012
• DOI: 10.1053/j.gastro.2020.10.036

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. 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. 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. 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. [Display omitted]