Intratumoral injection of interferon gamma promotes the efficacy of anti-PD1 treatment in colorectal cancer

作者：Yang Tang, Jingsun Wei, Xiaoxu Ge, Chengxuan Yu, Wei Lu, Yucheng Qian, Hang Yang, Dongliang Fu, Yimin Fang, Xinyi Zhou, Zhanhuai Wang, Qian Xiao, Kefeng Ding · 发表于：Cancer Letters · 年份：2024 · DOI：10.1016/j.canlet.2024.216798 · 被引用次数：17 · 研究领域：Cancer Immunotherapy and Biomarkers、Immune cells in cancer、Ferroptosis and cancer prognosis

Immune checkpoint inhibitors (ICIs) offer new options for the treatment of patients with solid cancers worldwide. The majority of colorectal cancers (CRC) are proficient in mismatch-repair (pMMR) genes, harbors few tumor antigens and is insensitive to ICIs. These tumors are often found to be immune-deserted. We hypothesized that forcing immune cell infiltration into the tumor microenvironment followed by immune ignition by PD1 blockade may initiate a positive immune cycle that can boost antitumor immunity. Bioinformatics using a public database suggested that IFNγ was a key indicator of immune status and prognosis in CRC. Intratumoral administration of IFNγ increased immune cells infiltration into the tumor, but upregulated PD-L1. A combined treatment strategy using IFNγ and anti-PD-1 antibody significantly increased T cell killing of tumor cells in vitro and showed synergistic inhibition of tumor growth in a mouse model of CRC. CyTOF found drastic changes in the immune microenvironment upon combined immunotherapy. Treatment with IFNγ and anti-PD1 antibody in CT26 tumors significantly increased infiltration of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). IFNγ had a more pronounced effect in decreasing intratumoral M2-like macrophages, while PD1 blockade increased the population of CD8+Ly6C + T cells in the tumor microenvironment, creating a more pro-inflammatory microenvironment. Additionally, PD1 induced increased lymphocyte activating 3 (LAG3) expression ...