Abstract 5134: PD-1/PD-L1 signalling axis, “a double-edged sword” in DSS induced colitis mouse model

Abstract

Abstract Background. Immune checkpoint molecules are essential for modulating immune responses and maintaining self-tolerance. While immune checkpoint inhibitors have improved the treatment of a broad spectrum of cancers, many of them are also believed to play a critical role in the induction of immune related adverse events (irAEs) such as autoimmune and inflammatory diseases. For example, patients receiving anti-PD-1 based therapy frequently develop colitis. In addition, dysfunctional PD-1 signalling has also been linked to increasing susceptibility to autoimmune and inflammatory diseases. Therefore, immune checkpoint molecule agonist which could, like their natural ligands, confer a great potential in suppressing excessively activated immune response observed in autoimmune and inflammatory diseases. Methods. In the first part, the proinflammation effects of a Pembrolizumab analogue was evaluated in a MC38-OVA colorectal tumor bearing mice treated with or without DSS. In the second part, an anti-hPD-1 agonistic antibody at 10 mg/kg was evaluated in acute DSS IBD model. Results. In the MC38-OVA colorectal cancer model, mice treated with Pembrolizumab analogue only or Pembrolizumab analogue plus 1.5% DSS showed significant tumor growth inhibition (100% TGI and 92.01% TGI, respectively at Day 27) compared to their respective control group, which suggests this Pembrolizumab analogue induced robust anti-tumor immunity against MC38-OVA tumors. Notably, 8/8 mice treated with Pembrolizumab analogue only showed complete tumor regression, while only 5/8 mice treated with Pembrolizumab analogue plus DSS showed complete tumor regression. Taken together, these results suggest DSS treatment leading to a proinflammatory context could compromise anti-hPD-1 anti-tumor efficacy. Moreover, mice treated with Pembrolizumab analogue plus DSS also showed 3.59% more Body Weight Loss (BWL) in comparison to 1.5% DSS only group, suggesting that Pembrolizumab analogue could exacerbate DSS induced colitis. In the acute DSS IBD model, mice treated with an agonistic anti-hPD-1 antibody showed significantly lower disease score (DAI 5.3 vs DAI 2.4) and less BWL (BWL 13.44% vs BWL 3.31%) in comparison to isotype control group. In addition, pathology results showed that mice treated with agonistic anti-hPD-1 exhibits significantly less inflammatory cell infiltration and colonic lesions when compared to isotype control group. Conclusion. In summary, we reported in this study that blocking of PD-L1/PD-1 signalling axis by a PD-1 antagonist activated T cell function which at the same time aggravated DSS induced colitis in mouse. In contrast, activation of PD-L1/PD-1 signalling pathway by a PD-1 agonist alleviated DSS induced colitis. Citation Format: Tao Yang, Rongfei Lu, kaixia lian, Likun Zhang, Dawei Wang, Xinhe Feng, Xiaoyu An, Jessie (Jingjing) Wang, Carl K. Edwards. PD-1/PD-L1 signalling axis, “a double-edged sword” in DSS induced colitis mouse model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5134.