Abstract 6646: Inhibition of HuR/CD147/IL-6 axis enhances anti-PD1 immunotherapy response in cancer

Abstract

Abstract Immune checkpoint blockade (ICB) targeting PD-1/PD-L1 has emerged as a revolutionizing treatment modality for multiple cancers. However, durable remission and objective response rates with ICB monotherapy remain low. Several immune resistance mechanisms have been revealed and used to develop combinational therapy. In consideration of the durable and impressive responses observed in ‘hot’ tumors, it will be valuable to make an endeavor to elucidate the tumor evasion mechanisms. Despite the well-established mechanisms in immunotherapy resistance, our study uncovered a new mechanism of tumor immune evasion through the RNA-binding protein HuR/CD147 axis. The RNA-binding protein Hu antigen R (HuR) is overexpressed in a variety of cancers and promotes tumorigenesis by interacting with a subset of oncogenic mRNAs. The tumor-associated antigen CD147, a highly glycosylated transmembrane immunoglobulin, is widely and specifically expressed in multiple malignancies. We phenotypically observed the downregulation of CD147 in HuR-deficient cells and elucidated that HuR regulates CD147 mRNA via binding to the AU-rich elements of its 3' UTR. The direct binding of HuR to CD147 mRNA in multiple types of cells was validated by Ribonucleoprotein immunoprecipitation (RNP-IP) and RNA pulldown assay. These data together clarify HuR is engaged in CD147 post-transcription regulation. KH-39 is a HuR-specific small molecule inhibitor, which disrupts the HuR function by competing for the binding site with its target mRNAs. KH-39 treatment reduced CD147 level in a time-/dose-dependent manner. We also tested the anti-tumor action of HuR small molecular inhibitor KH-39 in tumor proliferation, clonogenicity, cell death, cytokine secretion, and in vivo tumor growth. The cytokine array assay indicated multiple immune-related cytokines changed after HuR inhibition and CD147 knockdown, including IL-6, which is proven to act as an immunomodulating agent in the tumor microenvironment. These data demonstrated the potential mechanism of overcoming immunoresistance by inhibiting the HuR/CD147/IL-6 axis. To test the combination strategy using HuR inhibitor and anti-PD-1 antibody in vivo, we established the EMT6 orthotopic mouse breast cancer model. A combination of HuR inhibitor KH-39 and anti-PD-1 antibody enhanced the anti-PD1 immunotherapy response and prolonged survival compared to the single agent group. Taken together, we preliminarily explored the HuR/CD147/IL-6 axis in tumor immune evasion, which might be a promising therapeutic target to overcome immune evasion and improve immunotherapy response in cancer. This finding may have reference significance for clinical cancer therapy. Citation Format: Qi Zhang, Lauren Dandreo, Xiaoqing Wu, Liang Xu. Inhibition of HuR/CD147/IL-6 axis enhances anti-PD1 immunotherapy response in cancer [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 6646.