Protein Kinase C-θ Is Required for NK Cell Activation and In Vivo Control of Tumor Progression

Abstract

Protein kinase C-θ (PKCθ) was initially isolated as an important PKC isoform expressed in T cells, although its expression is not restricted to these cells. Despite the central function of PKCθ in several immune responses, its role in the antitumor response against MHC class I (MHC-I)-negative cells has not been investigated. This is an important issue because most tumor cells growing in vivo down-regulate MHC-I expression to escape the CTL-mediated response. In the present work, we show that in vivo development of a MHC-I-deficient tumor (RMA-S) is much favored in PKCθ−/− mice compared with wild-type mice. This is associated with a reduced recruitment of NK cells to the site of tumor development and a reduced activation status of recruited NK cells. This correlates with a reduced ex vivo and in vivo cytotoxic potential of NK cells isolated from PKCθ−/− mice treated with polyinosinic:polycytidylic acid. Consistently, polinosinic:cytidilic acid treatment induces PKCθ expression and activation of its enzymatic activity in NK cells in an indirect manner. These observations underline the relevance of PKCθ as a key molecule in NK cell-mediated antitumor immune surveillance.

IFNα signaling through PKC-θ is essential for antitumor NK cell function

“…In the latter scenario, the presence of the complete splenocyte immune population was apparently needed, suggesting that the effect is presumably partially mediated by macrophages and/or dendritic cells. 23 Our finding is in accord with previous studies demonstrating a NK cell-dependent increase in anticancer activity of NK cells responding to poly I:C stimulation. 25 PKC-u activation in this context is presumably mediated by soluble factor(s), which could be cytokine(s) secreted by macrophages and (or) dendritic cells (DCs) that are known to activate NK cells.…”

“…Furthermore, in vitro testing showed that NK cells isolated from PKC-u ¡/¡ mice exhibited reduced cytotoxicity against leukemic RMA-S cells after poly-inosinic:cytidiylic acid (poly I:C) treatment ex vivo. 23 We also observed that poly I:C treatment increased the relative expression levels and the activation status of PKC-u in NK cells, both in vivo and in vitro. In the latter scenario, the presence of the complete splenocyte immune population was apparently needed, suggesting that the effect is presumably partially mediated by macrophages and/or dendritic cells.…”

“…23,24 This pathophysiological condition was found to be associated with a deficient recruitment of NK cells to the tumor site in PKC-u ¡/¡ mice, correlating with impaired activation of recruited NK cells. Furthermore, in vitro testing showed that NK cells isolated from PKC-u ¡/¡ mice exhibited reduced cytotoxicity against leukemic RMA-S cells after poly-inosinic:cytidiylic acid (poly I:C) treatment ex vivo.…”

“…More importantly, in a mixed splenocyte culture stimulated ex vivo with poly I:C, neutralizing antibodies against IL-15 substantially reduced NK cell PKC-u phosphorylation, whereas IL-12 antibody blockade was ineffective. 23 Therefore, IL-15 appeared to be the most feasible candidate to mediate PKC-u-dependent antitumor NK cell immune function. 24 In the present study, we initially set out to test this possibility, testing IL-15 in regards to PKC-u activation status and NK cell immunophenotypes.…”

The anti-tumoral drug enzastaurin inhibits natural killer cell cytotoxicity via activation of glycogen synthase kinase-3β

“…In NK cells, the rapid activation of PKC enables them to mediate natural cytotoxicity towards tumor cells [65,66], and PKC activation is essential for triggering lysis in IL-2-activated NK cells [6]. PKCζ was also demonstrated to be required for NK cell activation and in vivo control of tumor progression [44]. Some other report described the absolute requirement of PKCζ for ITAM-mediated IFN-γ secretion, but without a marked influence on the release of cytolytic mediators [20].…”