The success of T cell-based cancer immunotherapy is limited by tumor's resistance against killing by cytotoxic T lymphocytes (CTLs). Tumor-immune resistance is mediated by cell surface ligands that engage immune-inhibitory receptors on T cells. These ligands represent potent targets for therapeutic inhibition. So far, only few immune-suppressive ligands have been identified.
We here describe a rapid high-throughput siRNA-based screening approach that allows a comprehensive identification of ligands on lung cancer cells that inhibit CTL-mediated tumor cell killing.
We demonstrate that IL6 exerts strong immune-regulatory effects on T cell responses in lung cancer. Unlike PDL1, which inhibits TCR signaling, IL6 regulates STAT3 in T cells, resulting in reduced T-helper-1 cytokine secretion and reduced cytotoxic capacity. Moreover, inhibition of IL6 expression on tumor cells facilitated immunotherapy of lung cancer by tumor-specific T cells in vivo.
Taken together, this method allows a rapid and comprehensive determination of immune-modulatory genes in lung tumor which represent the 'immune modulatome' of lung cancer.
Clinical trial identification
Legal entity responsible for the study
Open Fund of State Key Laboratory of Southern China Oncology
All authors have declared no conflicts of interest.