Signaling by ADAP via the Carma1-TAK1 axis is critical for pro-inflammatory cytokine production but not for cytotoxicity in NK cells. (IRM7P.477)

Abstract

‘Cytokine release syndrome’ (CRS) is a serious side effect of NK or T cell-mediated immunotherapy to treat cancer. A strategy to contain CRS without affecting the cytotoxic potential of NK and T cells is highly warranted. A thorough understanding of the signaling pathways will help to identify molecules that exclusively regulate inflammatory cytokine production but not cytotoxicity. Here, we define an ADAP-dependent signaling axis downstream of Fyn that exclusively regulated cytokine production but not cytotoxicity in NK cells. The adapter protein, ADAP is critical for organizing the Carma1-Bcl10-MALT1 signalosome, which is essential for the activation of TAK1. The initiation of these signaling events is critical for the production of Interferon-γ and other pro-inflammatory cytokines. The defect in cytokine production correlated with a decreased nuclear translocation of c-Fos and c-Jun despite a significantly increased phosphorylation of ERK1/2 and JNK1/2 in the ADAP deficient NK cells. Nuclear translocation of NFκB was also decreased in the ADAP deficient NK cells. Our findings indicate that ADAP is indispensible for activating a signaling cascade that leads to inflammatory cytokine production, whereas it is not essential for those signaling events that lead to cytotoxicity. Our findings demonstrate the feasibility of targeting the functions of unique signaling molecules in order to regulate the production of inflammatory cytokines.