Scrutinizing the Expression and Blockade of Inhibitory Molecules Expressed on T Cells from Acute Myeloid Leukemia Patients
-
Mohsen Abdolmaleki
,
Nazanin Mojtabavi
,
Mahdi Zavvar
,
Mohammad Vaezi
,
Farshid Noorbakhsh
,
Mohammad Hossein Nicknam
Abstract
T cell exhaustion is an immunosuppressive mechanism which occurs in chronic viral infections, solid tumors and hematologic malignancies. Exhausted T cell has increased the expression of inhibitory receptors, and functional impairment. In this study, we investigated the expression from some of those inhibitory receptors being Programmed death 1 (PD-1), T cell immunoglobulin and mucin domain containing molecules 3 (TIM-3) and CD244 on T cells from Iranian acute myeloid leukemia (AML) patients. Peripheral blood samples were collected from Iranian newly diagnosed AML patients and flow cytometric analysis was accomplished for cell surface expression of PD-1, TIM-3, and CD244 on T lymphocytes. Functionality and proliferation assay were done in the presence of anti-PD-1 and anti-CD244 blocking antibodies. Immunophenotyping of T cells showed a significant increase of PD-1 and CD244 expression on CD4+ and CD8+ T cells of AML patients. Whereas blockade of PD1 and CD244 increased the proliferation of CD4+ and CD8+ T lymphocytes of AML patients but IFN-γ production was not significantly increased. In conclusion, our data indicate that CD4+ and CD8+ T cells from AML patients appeared to be exhausted and blockade of some immune checkpoints can improve the proliferation of those cells.
1. Wherry EJ. T cell exhaustion. Nat Immunol 2011; 12(6):492-9.
2. Kong Y, Zhu L, Schell TD, Zhang J, Claxton DF, Ehmann WC, et al. T-Cell Immunoglobulin and ITIM Domain (TIGIT) Associates with CD8+ T-Cell Exhaustion and Poor Clinical Outcome in AML Patients. Clin Cancer Res 2016; 22(12):3057-66.
3. Yi JS, Cox MA, Zajac AJ. T-cell exhaustion: characteristics, causes and conversion. Immunology 2010; 129(4):474-81.
4. Ok CY, Young KH. Checkpoint inhibitors in hematological malignancies. J Hematol Oncol 2017; 10(1):103.
5. Schnorfeil FM, Lichtenegger FS, Emmerig K, Schlueter M, Neitz JS, Draenert R, et al. T cells are functionally not impaired in AML: increased PD-1 expression is only seen at time of relapse and correlates with a shift towards the memory T cell compartment. J Hematol Oncol 2015; 8:93.
6. Tan J CS, Xu L, Lu S, Zhang Y, Chen J, et al. Increasing Frequency of T Cell Immunosuppressive Receptor Expression in CD4+ and CD8+ T Cells May Related to T Cell Exhaustion and Immunosuppression in Patients with AML. Blood Cancer 2016; 128(22):5166.
7. Riches JC, Davies JK, McClanahan F, Fatah R, Iqbal S, Agrawal S, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood 2013; 121(9):1612-21.
8. Khaitan A, Unutmaz D. Revisiting immune exhaustion during HIV infection. Current HIV/AIDS Rep 2011; 8(1):4-11.
9. Javan MR, Aslani S, Zamani MR, Rostamnejad J, Asadi M, Farhoodi M, et al. Downregulation of Immunosuppressive Molecules, PD-1 and PD-L1 but not PD-L2, in the Patients with Multiple Sclerosis. IJAAI 2016; 15(4):296-302.
10. Tahoori MT, Pourfathollah AA, Akhlaghi M, Daneshmandi S, Nicknam MH, Soleimanifar N. Association of programmed cell death-1 (PDCD-1) gene polymorphisms with rheumatoid arthritis in Iranian patients. Clin Exp Rheumatol 2011; 29(5):763-7.
11. Soleimanifar N, Amirzargar AA, Mahmoudi M, Pourfathollah AA, Azizi E, Jamshidi AR, et al. Study of programmed cell death 1 (PDCD1) gene polymorphims in Iranian patients with ankylosing spondylitis. Inflammation 2011; 34(6):707-12.
12. Tsirigotis P, Savani BN, Nagler A. Programmed death-1 immune checkpoint blockade in the treatment of hematological malignancies. Ann Med 2016; 48(6):428-39.
13. Zhang F, Liu X, Chen C, Zhu J, Yu Z, Xie J, et al. CD244 maintains the proliferation ability of leukemia initiating cells through SHP-2/p27kip1 signaling. Haematologica 2017; 102(4):707-18.
14. Altvater B, Landmeier S, Pscherer S, Temme J, Schweer K, Kailayangiri S, et al. 2B4 (CD244) signaling by recombinant antigen-specific chimeric receptors costimulates natural killer cell activation to leukemia and neuroblastoma cells. Clin Cancer Res 2009; 15(15):4857-66.
15. Ferrara F, Schiffer CA. Acute myeloid leukaemia in adults. Lancet 2013; 381(9865):484-95.
16. Asakura S, Hashimoto D, Takashima S, Sugiyama H, Maeda Y, Akashi K, et al. Alloantigen expression on non-hematopoietic cells reduces graft-versus-leukemia effects in mice. T J Clin Invest 2010; 120(7):2370-8.
17. van de Veen W, Stanic B, Wirz OF, Jansen K, Globinska A, Akdis M. Role of regulatory B cells in immune tolerance to allergens and beyond. J Allergy Clin Iimmunol 2016; 138(3):654-65.
18. Koestner W, Hapke M, Herbst J, Klein C, Welte K, Fruehauf J, et al. PD-L1 blockade effectively restores strong graft-versus-leukemia effects without graft-versus-host disease after delayed adoptive transfer of T-cell receptor gene-engineered allogeneic CD8+ T cells. Blood 2011; 117(3):1030-41.
19. Mumprecht S, Schurch C, Schwaller J, Solenthaler M, Ochsenbein AF. Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression. Blood 2009; 114(8):1528-36.
20. Kozako T, Yoshimitsu M, Fujiwara H, Masamoto I, Horai S, White Y, et al. PD-1/PD-L1 expression in human T-cell leukemia virus type 1 carriers and adult T-cell leukemia/lymphoma patients. Leukemia 2009; 23(2):375-82.
21. Zhang L, Gajewski TF, Kline J. PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood 2009; 114(8):1545-52.
22. Shi L, Chen S, Yang L, Li Y. The role of PD-1 and PD-L1 in T-cell immune suppression in patients with hematological malignancies. J Hematol Oncol 2013; 6(1):74.
23. Yang H, Bueso-Ramos C, DiNardo C, Estecio MR, Davanlou M, Geng QR, et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia 2014; 28(6):1280-8.
24. Taghiloo S, Allahmoradi E, Tehrani M, Hossein-Nataj H, Shekarriz R, Janbabaei G, et al. Frequency and functional characterization of exhausted CD8+ T cells in chronic lymphocytic leukemia. Eur J Haematol 2017; 98(6):622-31.
25. Chibueze CE, Yoshimitsu M, Arima N. CD160 expression defines a uniquely exhausted subset of T lymphocytes in HTLV-1 infection. Biochem Biophys Res Commun 2014; 453(3):379-84.
26. Ezinne CC, Yoshimitsu M, White Y, Arima N. HTLV-1 specific CD8+ T cell function augmented by blockade of 2B4/CD48 interaction in HTLV-1 infection. PloS one 2014; 9(2):e87631.
27. Kong Y, Zhang J, Claxton DF, Ehmann WC, Rybka WB, Zhu L, et al. PD-1(hi) TIM-3(+) T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation. Blood Cancer 2015; 5:e330.
28. Paley MA, Kroy DC, Odorizzi PM, Johnnidis JB, Dolfi DV, Barnett BE, et al. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 2012; 338(6111):1220-5.
29. Blackburn SD, Shin H, Freeman GJ, Wherry EJ. Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade. Pro Natl Acad Sci U S A 2008; 105(39):15016-21.
30. Novak M, Prochazka V, Turcsanyi P, Papajik T. Numbers of CD8+PD-1+ and CD4+PD-1+ Cells in Peripheral Blood of Patients with Chronic Lymphocytic Leukemia Are Independent of Binet Stage and Are Significantly Higher Compared to Healthy Volunteers. Acta Hematol 2015; 134(4):208-14.
31. Paiva B, Azpilikueta A, Puig N, Ocio EM, Sharma R, Oyajobi BO, et al. PD-L1/PD-1 presence in the tumor microenvironment and activity of PD-1 blockade in multiple myeloma. Leukemia 2015; 29(10):2110-3.
32. Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med 2010; 207(10):2187-94.
| Files | ||
| Issue | Vol 17, No 3 (2018) | |
| Section | Original Article(s) | |
| Keywords | ||
| Acute myeloid leukemia CD244 PD-1 T cell exhaustion TIM-3 | ||
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