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 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.