Gal9/Tim-3 expression level is higher in AML patients who fail chemotherapy
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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2019-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-019-0611-3 |
| _version_ | 1818545131967479808 |
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| author | Paola Dama Marshall Tang Noreen Fulton Justin Kline Hongtao Liu |
| author_facet | Paola Dama Marshall Tang Noreen Fulton Justin Kline Hongtao Liu |
| author_sort | Paola Dama |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T22:57:31Z |
| format | Article |
| id | doaj.art-e8d2ccdbeeb942dda5ccfa646c2af6e6 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-11T22:57:31Z |
| publishDate | 2019-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-e8d2ccdbeeb942dda5ccfa646c2af6e62022-12-22T00:47:12ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-07-01711710.1186/s40425-019-0611-3Gal9/Tim-3 expression level is higher in AML patients who fail chemotherapyPaola Dama0Marshall Tang1Noreen Fulton2Justin Kline3Hongtao Liu4University of Chicago Medicine Hematology/Oncology SectionUniversity of Chicago Medicine Hematology/Oncology SectionUniversity of Chicago Medicine Hematology/Oncology SectionUniversity of Chicago Medicine Hematology/Oncology SectionUniversity of Chicago Medicine Hematology/Oncology SectionAbstract 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.http://link.springer.com/article/10.1186/s40425-019-0611-3Acute myeloid leukemiaChemotherapyImmune checkpointTreatment failureT-cellExhaustion |
| spellingShingle | Paola Dama Marshall Tang Noreen Fulton Justin Kline Hongtao Liu Gal9/Tim-3 expression level is higher in AML patients who fail chemotherapy Journal for ImmunoTherapy of Cancer Acute myeloid leukemia Chemotherapy Immune checkpoint Treatment failure T-cell Exhaustion |
| title | Gal9/Tim-3 expression level is higher in AML patients who fail chemotherapy |
| title_full | Gal9/Tim-3 expression level is higher in AML patients who fail chemotherapy |
| title_fullStr | Gal9/Tim-3 expression level is higher in AML patients who fail chemotherapy |
| title_full_unstemmed | Gal9/Tim-3 expression level is higher in AML patients who fail chemotherapy |
| title_short | Gal9/Tim-3 expression level is higher in AML patients who fail chemotherapy |
| title_sort | gal9 tim 3 expression level is higher in aml patients who fail chemotherapy |
| topic | Acute myeloid leukemia Chemotherapy Immune checkpoint Treatment failure T-cell Exhaustion |
| url | http://link.springer.com/article/10.1186/s40425-019-0611-3 |
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