title: NK-cell dysfunction in human renal carcinoma reveals diacylglycerol kinase as key regulator and target for therapeutic intervention.
abstract: The relevance of NK cells in tumor control is well established in mouse models and human hematologic malignancies; however, their contribution to the control of human solid tumors remains disputed due to problems with in situ detection and reports of functional inactivity in the tumor milieu. In this study, we established a reliable in situ detection method for NK cells. Moreover, we performed analysis to elucidate mechanisms that impair NK-cell function in the tumor milieu and thereby identify therapeutic targets that allow recovery of NK-cell functionality. It was observed that NK cells from clear cell renal cell carcinoma (ccRCC), compared to NK cells from nontumor kidney and peripheral blood lymphocytes (PBLs), displayed conjoint phenotypic alterations and dysfunction induced by the tumor milieu, which were associated mechanistically with high levels of signaling attenuator diacylglycerol kinase (DGK)-α and blunted mitogen-activated protein kinase pathway activation (ERK1/2, Jun kinase). Reinstating NK-cell functionality was possible by DGK inhibition or brief IL-2 culture, interventions that de-repressed the ERK pathway. The extent of alteration and magnitude of recovery could be linked to NK-cell frequency within ccRCC-infiltrating lymphocytes, possibly explaining the observed survival benefit of patients with NK(high) tumors. In conclusion, DGK-mediated dampening of the ERK pathway ensuing in NK-cell dysfunction was identified as an important escape mechanism in ccRCC. DGK and the ERK pathway thus emerge as promising therapeutic targets to restore suppressed NK-cell activity for the improvement of antitumor immunity.
authors.affiliation: Helmholtz Zentrum München, Germany Research Center for Environmental Health, Institute of Molecular Immunology, Munich, Germany.
authors.forename: Petra U
authors.initials: PU
authors.lastname: Prinz
authors.forename: Anna N
authors.initials: AN
authors.lastname: Mendler
authors.forename: Dorothee
authors.initials: D
authors.lastname: Brech
authors.forename: Ilias
authors.initials: I
authors.lastname: Masouris
authors.forename: Ralph
authors.initials: R
authors.lastname: Oberneder
authors.forename: Elfriede
authors.initials: E
authors.lastname: Noessner
mesh_terms: D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D015550:Cell Degranulation; D018920:Coculture Techniques; D019852:Diacylglycerol Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007376:Interleukin-2 / Q000502:physiology; D020014:K562 Cells; D007680:Kidney Neoplasms / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology*; D020935:MAP Kinase Signaling System; D058990:Molecular Targeted Therapy; D011379:Prognosis
chemical_list: D004791:Enzyme Inhibitors; D007376:Interleukin-2; D019852:Diacylglycerol Kinase
keywords: ERK signaling; diacylglycerol kinase; functional recovery; targeted intervention; tumor-infiltrating NK cells