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

Emilie Picard; Yann Godet; Caroline Laheurte; Magalie Dosset; Jeanne Galaine; Laurent Beziaud; Romain Loyon; Laura Boullerot; Elodie Lauret Marie Joseph; Laurie Spehner; Marion Jacquin; Guillaume Eberst; Béatrice Gaugler; Françoise Le Pimpec-Barthes; Elizabeth Fabre; Virginie Westeel; Anne Caignard; Christophe Borg; Olivier Adotévi

doi:10.1080/2162402X.2018.1527498

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

Oncoimmunology. 2018 Oct 19;8(2):e1527498. doi: 10.1080/2162402X.2018.1527498. eCollection 2019.

Authors

Emilie Picard¹, Yann Godet¹, Caroline Laheurte^{1

2}, Magalie Dosset¹, Jeanne Galaine¹, Laurent Beziaud¹, Romain Loyon¹, Laura Boullerot¹, Elodie Lauret Marie Joseph¹, Laurie Spehner¹, Marion Jacquin², Guillaume Eberst³, Béatrice Gaugler¹, Françoise Le Pimpec-Barthes⁴, Elizabeth Fabre⁵, Virginie Westeel^{1

3}, Anne Caignard⁶, Christophe Borg^{1

7}, Olivier Adotévi^{1

7}

Affiliations

¹ University Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, LabEx LipSTIC, Besançon, France.
² University Hospital of Besançon, INSERM CIC-1431 Clinical Investigation Center in Biotherapies, Besançon, France.
³ University Hospital of Besançon, Department of Pneumology, Besançon, France.
⁴ Service de Chirurgie Thoracique, AP-HP, Hôpital Européen Georges Pompidou, Paris, France.
⁵ Service d'Oncologie Médicale, AP-HP, Hôpital Européen Georges Pompidou, Paris, France.
⁶ INSERM, UMR1160, Institut Universitaire d'hématologie, Paris, France.
⁷ University Hospital of Besançon, Department of Medical Oncology, Besançon, France.

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.

Keywords: CD16; NK cells; NSCLC ; NKp46; prognosis.

Publication types

Research Support, Non-U.S. Gov't

Grants and funding

This work was supported by the Conseil Régional de Franche-Comté;Ligue Contre le Cancer;Assistance Publique des Hôpitaux de Paris;