Gene expression profiling upon knockdown of JAK1 in IM9 cells

Natural Killer (NK) cells are primary effectors of innate immunity directed against transformed cells. In response, tumor cells have developed mechanisms to evade NK cell-mediated lysis but the molecular basis for target cell resistance is not well understood. In the present study, we used a lentiviral shRNA library targeting more than 1000 human genes to identify 83 genes that promote target cell resistance to human NK cells. Many of the genes identified in this genetic screen belong to common signaling pathways, however, none of these genes have previously been known to modulate susceptibility of human tumor cells to immunologic destruction. In particular, gene silencing of two members of the JAK family (JAK1 and JAK2) in a variety of tumor cell targets increased their susceptibility to NK-mediated lysis and induced increased secretion of interferon gamma (IFN-gamma by NK cells. Treatment of tumor cells with JAK inhibitors also induced increased susceptibility to NK cell activity. These findings may have important clinical implications and suggest that small molecule inhibitors of tyrosine kinases being developed as therapeutic anti-tumor agents may also have significant immunologic effects in vivo.

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Bellucci R, Nguyen HN, Martin A, Heinrichs S, Schinzel AC, Hahn WC, Ritz J