Novel Lymphocyte-Independent Antitumor Activity by PD-1 Blocking Antibody against PD-1+Chemoresistant Lung Cancer Cells

Purpose: Antibodies against the lymphocyte PD-1 (aPD-1) receptor are cornerstone agents for advanced non-small cell lung cancer (NSCLC), based on their ability to restore the exhausted antitumor immune response. Our study reports a novel, lymphocyte-independent, therapeutic activity of aPD-1 against NSCLC, blocking the tumor-intrinsic PD-1 receptors on chemoresistant cells.Experimental Design: PD-1 in NSCLC cells was explored in vitro at baseline, including stem-like pneumospheres, and following treatment with cisplatin both at transcriptional and protein levels. PD-1 signaling and RNA sequencing were assessed. The lympho-cyte-independent antitumor activity of aPD-1 was explored in vitro, by PD-1 blockade and stimulation with soluble ligand (PD-L1s), and in vivo within NSCLC xenograft models.Results: We showed the existence of PD-1+ NSCLC cell subsets in cell lines and large in silico datasets (Cancer Cell Line Encyclo-pedia and The Cancer Genome Atlas). Cisplatin significantly increased PD-1 expression on chemo-surviving NSCLC cells (2.5-fold P = 0.0014), while the sequential treatment with anti- PD-1 Ab impaired their recovery after chemotherapy. PD-1 was found to be associated with tumor stemness features. PD-1 expres-sion was enhanced in NSCLC stem-like pneumospheres (P < 0.0001), significantly promoted by stimulation with soluble PD -L1 (+27% +/- 4, P < 0.0001) and inhibited by PD-1 blockade (-30% +/- 3, P < 0.0001). The intravenous monotherapy with anti-PD-1 significantly inhibited tumor growth of NSCLC xenografts in immunodeficient mice, without the contribution of the immune system, and delayed the occurrence of chemoresistance when combined with cisplatin.Conclusions: We report first evidence of a novel lymphocyte -independent activity of anti-PD-1 antibodies in NSCLC, capable of inhibiting chemo-surviving NSCLC cells and exploitable to contrast disease relapses following chemotherapy.

Automated summary

This study reports a novel therapeutic activity of anti-PD-1 antibodies against non-small cell lung cancer (NSCLC), which can block the tumor-intrinsic PD-1 receptors on chemoresistant cells. PD-1 expression in NSCLC cells was found to increase after cisplatin treatment, and anti-PD-1 antibodies can inhibit the recovery of chemo-surviving cells. The study suggests that anti-PD-1 antibodies have a lymphocyte-independent activity in NSCLC and can be used to prevent disease relapses after chemotherapy.