Upregulation of PD‐1 follows tumour development in the AOM/DSS model of inflammation‐induced colorectal cancer in mice

Abstract

Summary Chronic inflammation may drive development of cancer as observed in inflammation‐induced colorectal cancer (CRC). Though immune cells can infiltrate the tumour microenvironment, cancer cells seem to evade anti‐tumour responses, which is one of the established hallmarks of cancer. Targeting the programmed cell death protein‐1 (PD‐1)/PD‐L1 signalling pathway is currently at the forefront in the development of anti‐tumour immunity‐based therapies for multiple malignancies. By blocking the immune‐checkpoint of activated T‐cells, it is possible to rewire the adaptive resistance induced by the PD‐1 ligands expressed in the tumour microenvironment. However, adverse immunotherapy‐modulated events could complicate the treatment of individuals with preexisting chronic inflammatory conditions. In this study, we investigated the expression of different systemic and mucosal T‐cell subsets during the course of azoxymethane (AOM)/dextran sulphate sodium (DSS)‐induced colitis and colitis‐associated CRC. In addition, we examined the expression of PD‐1 and its ligands PD‐L1 and PD‐L2 as well as other molecular targets related to T‐cell exhaustion. We found a significant increase in PD‐1 expression on all examined mucosal T‐cell subsets of the colon and the ileum, which correlated with disease progression. We also observed an upregulation of PD‐L1 and PD‐L2 mRNA expression throughout the AOM/DSS regime. Blocking PD‐1 signalling with an anti‐PD1 antibody did not affect the tumour burden in the AOM/DSS‐treated mice, but did potentiate the weight loss in the third DSS cycle, indicating possible immune‐mediated toxicity. This raises a concern for patients with colitis‐associated CRCs and should be further investigated.

A purified membrane protein from Akkermansia muciniphila or the pasteurised bacterium blunts colitis associated tumourigenesis by modulation of CD8+ T cells in mice

“… 18 The expression of PD-1 was upregulated on mucosal CD4, CD8αβ and TCRαβ cells of the colon and the ileum, which correlated with CAC progression. 43 Although the majority of CRCs with high CTLs infiltration have favourable outcomes, those with concurrently high PD-L1 gene expression have poor clinical outcomes. 44 In the present study, the proportion of PD-1 + CTLs was significantly reduced in CAC mice treated with pasteurised A. muciniphila or Amuc_1100.…”

Prognostic Impact of PD-1 and Tim-3 Expression in Tumor Tissue in Stage I-III Colorectal Cancer

“…However, the ligand-receptor interaction can inhibit activity of PD-1 + TILs and silence the immune system [10]. Yassin et al have found that PD-1 is upregulated following tumor development and the increase of PD-1 expression is associated with tumor progression in inflammationinduced CRC in mice [11]. In addition, evidence has shown that high expression of PD-1 is associated with poor prognosis in primary central nervous system lymphoma (PCNSL) and esophageal cancer [12,13].…”

Low Molecular Weight Dextran Sulfate (ILB®) Administration Restores Brain Energy Metabolism Following Severe Traumatic Brain Injury in the Rat

“…In ILB ® , sulfur represents~17% of its total mass. While high molecular weight dextran sulfate possesses toxic effects, inducing cancer development and inflammation [31][32][33], ILB ® is a proven safe and well-tolerated LMW-DS. Previous studies showed that LMW-DS dose-dependently limits the instant blood-mediated inflammatory reaction (IBMIR) [34,35], inhibits E-selectin-mediated adhesion of neutrophils to endothelial cells [36,37], prevents adherence of peritoneal metastases [38], and improves the effectiveness of therapy and reduces mortality in patients with acute cerebral infarction treated with the thrombolytic agent urokinase [39].…”