Tumor-Experienced Human NK Cells Express High Levels of PD-L1 and Inhibit CD8+ T Cell Proliferation.

Jessica Mariel Sierra ,Aldana Trotta,Florencia Secchiari,Hernando Ríos Pita,Carlos Ameri,Andrea Ziblat,Nicolás Richards,Nicolás I Torres,Ximena L Raffo Iraolagoitia,Mariana Gantov,María Victoria Regge ,Luís Rico ,Norberto Walter Zwirner ,Gonzálo Vitagliano ,A Friedrich ,Agustín Roberto Rovegno ,Maria Cecilia Santilli ,Sol Yanel Nuñez ,Carolina Inés Domaica ,Mercedes Fuertes

doi:10.3389/fimmu.2021.745939

Abstract

Natural Killer (NK) cells play a key role in cancer immunosurveillance. However, NK cells from cancer patients display an altered phenotype and impaired effector functions. In addition, evidence of a regulatory role for NK cells is emerging in diverse models of viral infection, transplantation, and autoimmunity. Here, we analyzed clear cell renal cell carcinoma (ccRCC) datasets from The Cancer Genome Atlas (TCGA) and observed that a higher expression of NK cell signature genes is associated with reduced survival. Analysis of fresh tumor samples from ccRCC patients unraveled the presence of a high frequency of tumor-infiltrating PD-L1+ NK cells, suggesting that these NK cells might exhibit immunoregulatory functions. In vitro, PD-L1 expression was induced on NK cells from healthy donors (HD) upon direct tumor cell recognition through NKG2D and was further up-regulated by monocyte-derived IL-18. Moreover, in vitro generated PD-L1hi NK cells displayed an activated phenotype and enhanced effector functions compared to PD-L1- NK cells, but simultaneously, they directly inhibited CD8+ T cell proliferation in a PD-L1-dependent manner. Our results suggest that tumors might drive the development of PD-L1-expressing NK cells that acquire immunoregulatory functions in humans. Hence, rational manipulation of these regulatory cells emerges as a possibility that may lead to improved anti-tumor immunity in cancer patients.

Highlights

Natural killer (NK) cells represent the cytotoxic lineage of innate lymphoid cells (ILC) [1] and play a pivotal role as effector cells against tumors and virus-infected cells
We recently demonstrated that in mice NK cells can acquire a regulatory phenotype characterized by a tumor-induced upregulation of Programmed Death-Ligand 1 (PD-L1) [30]
We previously demonstrated that tumor-infiltrating NK cells (TINK) express PD-L1 and inhibit anti-tumor T cell responses

Summary

Introduction

Natural killer (NK) cells represent the cytotoxic lineage of innate lymphoid cells (ILC) [1] and play a pivotal role as effector cells against tumors and virus-infected cells. Recent observations demonstrated a regulatory role for NK cells in diverse models of viral infection [14,15,16,17], transplantation [18] and autoimmunity [19]. Evidence about a regulatory function of NK cells during tumor growth remains poorly explored [29]. In this context, we have recently identified a subset of Programmed Death-Ligand 1 (PD-L1)-expressing NK cells, that arise in tumor bearing mice which can inhibit tumorspecific CD8+ T cell priming [30]

Methods

Results

Conclusion