Circulating NKp46⁺Natural Killer cells have a potential regulatory property and predict distinct survival in Non-Small Cell Lung Cancer

Abstract

Natural killer (NK) cells are innate effector lymphocytes widely involved in cancer immunosurveillance. In this study, we described three circulating NK cell subsets in patients with non-small cell lung cancer (NSCLC). Compared to healthy donors (HD), lower rate of the cytotoxic CD56 dim CD16 + NK cells was found in NSCLC patients (76.1% vs 82.4%, P = 0.0041). In contrast, the rate of CD56 bright NK cells was similar between patients and HD. We showed in NSCLC patients a higher rate of a NK cell subset with CD56 dim CD16 − phenotype (16.7% vs 9.9% P = 0.0001). The degranulation property and cytokines production were mainly drive by CD56 dim CD16 − NK cell subset in patients. Analysis of natural cytotoxicity receptors (NCRs) expression identified four distinct clusters of patients with distinct NK cell subset profiles as compared to one major cluster in HD. Notably the cluster characterized by a low circulating level of NKp46 + NK cell subsets was absent in HD. We showed that the rate of circulating NKp46 + CD56 dim CD16 + NK cells influenced the patients' survival. Indeed, the median overall survival in patients exhibiting high versus low level of this NK cell subset was 16 and 27 months respectively (P = 0.02). Finally, we demonstrated that blocking NKp46 receptor in vitro was able to restore spontaneous tumor specific T cell responses in NSCLC patients. In conclusion, this study showed a distinct distribution and phenotype of circulating NK cell subsets in NSCLC. It also supports the regulatory role of NKp46 + NK cell subset in NSCLC patients.

PD-1 checkpoint blockade in advanced melanoma patients: NK cells, monocytic subsets and host PD-L1 expression as predictive biomarker candidates

“…In line with our data, a recent study reported that NKp46 + NK cells were inversely correlated with survival in NSCLC. 38 Adotévi and collaborators highlight the possible regulatory role that soluble factors produced by NKp46 + NK cells may have in the expansion and activation of T cells, as has been previously suggested. 39,40 Besides NK cells, different subsets within the myeloid compartment were observed to be correlated with responses to PD-1 blockade.…”

Natural killer cells in the human lung tumor microenvironment display immune inhibitory functions

“…Finally, in advanced NSCLC, a regulatory role of NKp46 +NK cells has been reported, showing that low rates of circulating NKp46 + NK cells significantly associated with better OS. 50 …”

Regulatory functions of NK cells during infections and cancer

“…90 In addition, a higher frequency of a population of circulating NKp46 + CD56 dim CD16 + NK cells was associated with a decreased overall survival in patients with non-small cell lung cancer (NSCLC), and NKp46 blockade enhanced IFN-production by tumor antigen-specific CD4 T cells in cultures of patientderived PBMC. 91 A recent study shows that tumor-infiltrating NK cells from breast cancer patients display an increased expression of the 5 ′ ectonucleotidase CD73, accompanied by up-regulation of other immune checkpoint receptors such as LAG-3, VISTA, PD-1, and PD-L1. 92 The induction of enzymatically active CD73 was dependent on 4-1BBL recognition on tumor cells and CD73 + NK cells were able to inhibit CD4 T cell proliferation and IFN-production, but the inhibition was not dependent on the production of extracellular adenosine by CD73 activity.…”