Peripheral natural killer cells and myeloid-derived suppressor cells correlate with anti-PD-1 responses in non-small cell lung cancer

Abstract

Inhibition of immune checkpoint proteins like programmed death 1 (PD-1) is a promising therapeutic approach for several cancers, including non-small cell lung cancer (NSCLC). Although PD-1 ligand (PD-L1) expression is used to predict anti-PD-1 therapy responses in NSCLC, its accuracy is relatively less. Therefore, we sought to identify a more accurate predictive blood biomarker for evaluating anti-PD-1 response. We evaluated the frequencies of T cells, B cells, natural killer (NK) cells, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), mononuclear myeloid-derived suppressor cells (M-MDSCs), and Lox-1+ PMN-MDSCs in peripheral blood samples of 62 NSCLC patients before and after nivolumab treatment. Correlation of immune-cell population frequencies with treatment response, progression-free survival, and overall survival was also determined. After the first treatment, the median NK cell percentage was significantly higher in responders than in non-responders, while the median Lox-1+ PMN-MDSC percentage showed the opposite trend. NK cell frequencies significantly increased in responders but not in non-responders. NK cell frequency inversely correlated with that of Lox-1+ PMN-MDSCs after the first treatment cycle. The NK cell-to-Lox-1+ PMN-MDSC ratio (NMR) was significantly higher in responders than in non-responders. Patients with NMRs ≥ 5.75 after the first cycle had significantly higher objective response rates and longer progression-free and overall survival than those with NMRs <5.75. NMR shows promise as an early predictor of response to further anti-PD-1 therapy.

Prospective development and validation of a liquid immune profile-based signature (LIPS) to predict response of patients with recurrent/metastatic cancer to immune checkpoint inhibitors

“…Just recently, it was shown for patients with NSCLC that increased amounts of peripheral NK cells correlate with responses to anti-PD-1 treatment. 45 The role for NKT cells in this scenario has not been investigated before, but it is becoming more and more evident that NKT cells are important in antitumor immunity as they, for example, reinvigorate exhausted immune cells in the tumor microenvironment. 46 Exhausted immune cells fail to contribute to antitumor immunity.…”

Blocking Migration of Polymorphonuclear Myeloid-Derived Suppressor Cells Inhibits Mouse Melanoma Progression

“…Such increase in NK cell infiltration resulted in reduced primary tumor growth and metastasis. In addition, an increased ratio of NK cells to LOX-1 + PMN-MDSC predicted positive therapy response of patients with non-small cell lung carcinoma, indicating an important role of NK cell inhibition by PMN-MDSC in tumor progression [ 50 ]. Although CXCR2 was reported to be expressed also on the vascular endothelium, contributing to tumor angiogenesis [ 34 ], we failed to observe any changes in the frequency of CD31 + tumor infiltrating endothelial cells upon CXCR2 inhibition.…”

Development of a Flow Cytometry-Based Whole-Blood Prognostic Immune Signature in Metastatic Cancer Patients treated with immune checkpoint inhibitors

“…We identified increased numbers of NKT cells in patients of the ST-ICI trial to be favorable for PFS and OS. Just recently, it was shown for patients with NSCLC that increased amounts of peripheral NK cells correlate with responses to anti-PD-1 treatment [42]. The role for NKT cells in this scenario has not been investigated before, but it is becoming more and more evident that NKT cells are important in anti-tumor immunity as they e.g.…”