Folgiero Valentina, Cifaldi Loredana, Li Pira Giuseppina, Goffredo Bianca Maria, Vinti Luciana, Locatelli Franco
Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital, Viale di San Paolo 15, 00146, Rome, Italy.
Department of Laboratory Medicine, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
J Hematol Oncol. 2015 Apr 16;8:36. doi: 10.1186/s13045-015-0134-4.
NK cells expressing TIM-3 show a marked increase in IFNγ production in response to acute myeloid leukemia (AML) blast cells that endogenously express Gal-9. Herein, we demonstrate that NK cell-mediated production of IFNγ, induced by TIM-3/Gal-9 interaction and released in bone marrow microenvironment, is responsible for IDO1 expression in AML blasts. IDO1-expressing AML blasts consequently down-regulate NK cell degranulation activity, by sustaining leukemia immune escape. Furthermore, the blocking of TIM-3/Gal-9 interaction strongly down-regulates IFNγ-dependent IDO1 activity. Thus, the inhibition of TIM-3/Gal-9 immune check point, which affects NK cell-dependent IFNγ production and the consequent IDO1 activation, could usefully integrate current chemotherapeutic approaches.
表达TIM-3的自然杀伤细胞（NK细胞）在响应内源性表达半乳糖凝集素-9（Gal-9）的急性髓系白血病（AML）原始细胞时，其γ干扰素（IFNγ）产生显著增加。在此，我们证明，由TIM-3/Gal-9相互作用诱导并在骨髓微环境中释放的NK细胞介导的IFNγ产生，是AML原始细胞中吲哚胺2,3-双加氧酶1（IDO1）表达的原因。表达IDO1的AML原始细胞通过维持白血病免疫逃逸，从而下调NK细胞脱颗粒活性。此外，阻断TIM-3/Gal-9相互作用可强烈下调IFNγ依赖性IDO1活性。因此，抑制TIM-3/Gal-9免疫检查点，这会影响NK细胞依赖性IFNγ产生以及随之而来的IDO1激活，可能会有效地整合当前的化疗方法。
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