A high-throughput RNAi screen for detection of immune-checkpoint molecules that mediated to cytotoxic T lymphocytes in lung cancer

Background

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.

Methods

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.

Results

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.

Conclusions

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

NO

Legal entity responsible for the study

N/A

Funding

Open Fund of State Key Laboratory of Southern China Oncology

Disclosure

All authors have declared no conflicts of interest.