Gal9/Tim-3 expression level is higher in AML patients who fail chemotherapy. Issue 1 (10th July 2019)

• Record Type: Journal Article
• Authors: Dama, Paola; Tang, Marshall; Fulton, Noreen; Kline, Justin; Liu, Hongtao
• Is Part Of: Journal for immunotherapy of cancer. Volume 7:Issue 1(2019)
• Publication Date: 2019-07-10
• Subjects: Acute myeloid leukemia -- Chemotherapy -- Immune checkpoint -- Treatment failure -- T-cell -- Exhaustion -- Beyond PD-1 -- TIM-3; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1186/s40425-019-0611-3
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Immune checkpoint pathways active in Acute Myeloid Leukemia (AML) patients, especially during the course of remission induction chemotherapy, have not been well studied. Although dominant in mediating T cell dysfunction in cancer, it is now well-accepted that interruption of PD-1/PD-L1 axes alone does not always completely restore T cell function, indicating the involvement of additional negative regulatory pathways, such as TIM-3/Gal-9, in promoting T cell exhaustion. Here, we characterized these pathways in AML patients enrolled in a phase I dose escalation trial that combined Selinexor, a Selective Inhibitor of Nuclear Export (SINE), with high-dose cytarabine (HiDAC) and mitoxantrone (Mito) (NCT02573363 ) as induction therapy. To monitor changes in expression of immune checkpoint receptors, multi-parameter flow cytometry was performed on peripheral blood and bone marrow biopsy specimens at diagnosis and following induction therapy in 26 AML patients. Expression of CD47, PD-L1, PD-L2 and Gal9 was assessed on CD34 + AML blasts, as well as on CD34 − cell populations. In parallel, we evaluated expression of inhibitory (PD1, CTLA4, LAG3, TIM-3) and stimulatory (CD28, ICOS, CD137, OX40, CD40L, HLA-DR) co-receptors on CD4 + and CD8 + T cell subsets. Compared to baseline, the frequency of Gal9 + CD34 − cells was significantly higher in patients with treatment failure (TF) than in those in complete remission (CR), and this finding correlated with increased TIM-3 expression on marrow-resident T cells in TF patients. Moreover, when we measured the expression level of PD-1 and TIM-3 in bone marrow samples compared to peripheral blood, TIM-3 was significantly higher in BM specimens. Our results suggest that targeting the Gal9/Tim-3 axis could be effective in combination with induction chemotherapy to increase the likelihood of complete remission in AML patients.