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)-a 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.

DGK-α: A Checkpoint in Cancer-Mediated Immuno-Inhibition and Target for Immunotherapy

“…They play a complementary role to CD8-T cells as they recognize tumors which are resistant to T-cell killing due to downregulation or loss of MHC-class I molecules (refs. in Prinz et al, 2014). In some tumor types, such as RCC, they appear to play a prominent role as their number is predictive of good prognosis while that of CD8-T cells is not (Nakano et al, 2001; Eckl et al, 2012).…”

Redundant and specialized roles for diacylglycerol kinases α and ζ in the control of T cell functions

“…In these studies, the treatment of TILs with DGK inhibitors promoted ERK activation and the delivery of cytotoxic granules. DGKa acts similarly in the hypofunctional phenotype of tumor-infiltrating NK cells (104). The importance of DGK function to the hypofunctional state of TILs was confirmed by studies of human CAR T cells.…”

Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers

“…These innate immune cells represent a relevant percentage of the RCC TILs (Cózar et al, 2005;Van den Hove et al, 1997), and they often coexpress activation and inhibitory markers (Prinz et al, 2014;Schleypen et al, 2006;Van den Hove et al, 1997).…”