CNOT4 enhances the efficacy of anti-PD-1 immunotherapy in a model of non-small cell lung cancer.

Abstract

The use of immune checkpoint inhibitors that target programmed cell death-1 (PD-1) has been proposed for the treatment of advanced non-small cell lung cancer (NSCLC). However, in clinical trials, cumulative response rates to anti-PD-1 treatment were approximately 20% in patients with NSCLC. CCR4-NOT transcription complex, subunit 4 (CNOT4) is a RING finger protein with E3 ubiquitin ligase activity. We previously reported that CNOT4 may act as a tumor suppressor in NSCLC. Here, we examined whether CNOT4 can enhance the efficacy of anti-PD-1 immunotherapy in a model of NSCLC. The association of CNOT4 and overall survival was analyzed using datasets from The Cancer Genome Atlas (TCGA). Tumor models were established by subcutaneously implanting tumor cells line (A549 cell) into mice. CNOT4 was observed to be positively associated with relapse-free survival and overall survival in patients with NSCLC. CNOT4 overexpression suppressed tumor growth invivo and enhanced the effect of anti-PD-1 immunotherapy, which was accompanied by increased CD3+ and CD8+ T lymphocyte infiltration and higher interferon-γ and tumor necrosis factor-α levels. In conclusion, CNOT4 may enhance the efficacy of anti-PD-1 immunotherapy and may have potential as a prognostic marker for NSCLC, or as a combinational target with anti-PD-1 treatment for patients with NSCLC.