The Effects of PI3K/Akt/mTOR Signaling Pathway Inhibitors on the Expression of Immune Checkpoint Ligands in Acute Myeloid Leukemia Cell Line
Abstract
Up-regulation of immune checkpoint ligands is considered as one of the most important immune escape mechanisms in acute myeloid leukemia (AML). Herein, we investigate a relationship between the inhibition of PI3K/Akt/mTOR signaling pathways and the regulation of immune checkpoint ligands in AML cells.
The HL-60 cell line was treated with idelalisib as PI3K inhibitor, MK-2206 as Akt inhibitor, and everolimus as mTOR inhibitor either in a single or combined format. Cell viability and apoptosis were evaluated using MTT and flow cytometry assays, respectively. The relative expression of PD-L1, galectin-9, and CD155 was determined by real-time PCR.
Our findings demonstrated decreased proliferation and increased apoptosis of HL-60 cells after treatment with idelalisib, MK-2206, and everolimus. As expected, the combined treatment showed a more inhibiting effect than the single treatment. Interestingly, our results elucidated that the expression of PD-L1 and Gal-9 but not MK-2206 decreased after treatment with idelalisib and everolimus. Regarding CD155, the expression of this molecule was downregulated after treatment with everolimus, but not idelalisib and MK-2206. However, combined treatment of HL-60 cells with two or three inhibitors decreased the expression levels of PD-L1, Gal-9, and CD155 checkpoint ligands.
We showed that PI3K/Akt/mTOR pathway inhibitors not only serve as cytotoxic drugs but also regulate the expression of immune checkpoint ligands and interfere with the immune evasion mechanisms of AML leukemic cells. Combinational treatment approaches to block these pathways might be a promising and novel therapeutic strategy for AML patients via interfering in immune escape mechanisms.
1. Luppi M, Fabbiano F, Visani G, Martinelli G, Venditti A. Novel agents for acute myeloid leukemia. Cancers. 2018;10(11):429.
2. Saultz J, Garzon R. Acute myeloid leukemia: a concise review. J Clin Med. 2016;5(3):33.
3. Deng L, Jiang L, Lin X-h, Tseng K-F, Liu Y, Zhang X, et al. The PI3K/mTOR dual inhibitor BEZ235 suppresses proliferation and migration and reverses multidrug resistance in acute myeloid leukemia. Acta Pharmacol Sin. 2017;38(3):382.
4. Feldman EJ. Novel therapeutics for therapy-related acute myeloid leukemia: 2014. Clin Lymphoma Myeloma Leuk. 2015;15:S91-S3.
5. Sandhöfer N, Metzeler K, Rothenberg M, Herold T, Tiedt S, Groiss V, et al. Dual PI3K/mTOR inhibition shows antileukemic activity in MLL-rearranged acute myeloid leukemia. Leukemia. 2015;29(4):828-38.
6. Khaled S, Monzr Al Malki M, Marcucci G. Acute myeloid leukemia: biologic, prognostic, and therapeutic insights. Oncology. 2016;30(4).
7. Bertacchini J, Heidari N, Mediani L, Capitani S, Shahjahani M, Ahmadzadeh A, et al. Targeting PI3K/AKT/mTOR network for treatment of leukemia. Cell Mol Life Sci. 2015;72(12):2337-47.
8. Brenner A, Andersson Tvedt T, Bruserud Ø. The complexity of targeting PI3K-Akt-mTOR signalling in human acute myeloid leukaemia: the importance of leukemic cell heterogeneity, neighbouring mesenchymal stem cells and immunocompetent cells. Molecules. 2016;21(11):1512.
9. Polak R, Buitenhuis M. The PI3K/PKB signaling module as key regulator of hematopoiesis: implications for therapeutic strategies in leukemia. Blood. 2012;119(4):911-23.
10. Nepstad I, Reikvam H, Brenner A, Bruserud Ø, Hatfield K. Resistance to the antiproliferative in vitro effect of PI3K-Akt-mTOR inhibition in primary human acute myeloid leukemia cells is associated with altered cell metabolism. Int Mol Sci. 2018;19(2):382.
11. Brotelle T, Bay J-O. PI3K-AKT-mTOR pathway: Description, therapeutic development, resistance, predictive/prognostic biomarkers and therapeutic applications for cancer. Bull Cancer. 2016;103(1):18-29.
12. Dos Santos C, Récher C, Demur C, Payrastre B. The PI3K/Akt/mTOR pathway: a new therapeutic target in the treatment of acute myeloid leukemia. Bull Cancer. 2006;93(5):445-7.
13. Smyth MJ, Dunn GP, Schreiber RD. Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol. 2006;90:1-50.
14. A Knaus H, G Kanakry C, Luznik L, Gojo I. Immunomodulatory drugs: immune checkpoint agents in acute leukemia. Curr Drug Targets. 2017;18(3):315-31.
15. Jiang X, Wang J, Deng X, Xiong F, Ge J, Xiang B, et al. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol Cancer. 2019;18(1):10.
16. Taghiloo S, Asgarian-Omran H. Immune evasion mechanisms in Acute Myeloid Leukemia; a focus on immune checkpoint pathways. Crit Rev Oncol Hematol. 2020:103164.
17. Teague RM, Kline J. Immune evasion in acute myeloid leukemia: current concepts and future directions. J Immunother Cancer. 2013;1(1):13.
18. Rajabian Z, Kalani F, Taghiloo S, Tehrani M, Rafiei A, Hosseini-Khah Z, et al. Over-expression of immunosuppressive molecules, PD-L1 and PD-L2, in ulcerative colitis patients. Iran J Immunol. 2019;16(1):62-70.
19. 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.
20. Beatty GL, Gladney WL. Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res. 2015;21(4):687-92.
21. Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol Immunother. 2005;54(4):307-14.
22. Drake CG, Jaffee E, Pardoll DM. Mechanisms of immune evasion by tumors. Adv Immunol. 2006;90:51-81.
23. Peng S, Wang R, Zhang X, Ma Y, Zhong L, Li K, et al. EGFR-TKI resistance promotes immune escape in lung cancer via increased PD-L1 expression. Mol. Cancer. 2019;18(1):165.
24. Dong L, Lv H, Li W, Song Z, Li L, Zhou S, et al. Co-expression of PD-L1 and p-AKT is associated with poor prognosis in diffuse large B-cell lymphoma via PD-1/PD-L1 axis activating intracellular AKT/mTOR pathway in tumor cells. Oncotarget. 2016;7(22):33350.
25. Barrett D, Brown VI, Grupp SA, Teachey DT. Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies. Paediatr Drugs. 2012;14(5):299-316.
26. Herschbein L, Liesveld JL. Dueling for dual inhibition: Means to enhance effectiveness of PI3K/Akt/mTOR inhibitors in AML. Blood Rev. 2018;32(3):235-48.
27. Martelli AM, Evangelisti C, Chiarini F, McCubrey JA. The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients. Oncotarget. 2010;1(2):89.
28. Park S, Chapuis N, Tamburini J, Bardet V, Cornillet-Lefebvre P, Willems L, et al. Role of the PI3K/AKT and mTOR signaling pathways in acute myeloid leukemia. haematologica. 2010;95(5):819-28.
29. Lang F, Wunderle L, Badura S, Schleyer E, Brüggemann M, Serve H, et al. A phase I study of a dual PI3-kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia. BMC pharmacol. 2020;21(1):1-14.
30. Chapuis N, Tamburini J, Green AS, Vignon C, Bardet V, Neyret A, et al. Dual inhibition of PI3K and mTORC1/2 signaling by NVP-BEZ235 as a new therapeutic strategy for acute myeloid leukemia. Clin Cancer Res. 2010;16(22):5424-35.
31. Hao Y, Zhang N, Wei N, Yin H, Zhang Y, Xu H, et al. Matrine induces apoptosis in acute myeloid leukemia cells by inhibiting the PI3K/Akt/mTOR signaling pathway. Oncol. Lett. 2019;18(3):2891-6.
32. Martelli AM, Tazzari P, Evangelisti C, Chiarini F, Blalock W, Billi A, et al. Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin module for acute myelogenous leukemia therapy: from bench to bedside. Curr Med Chem. 2007;14(19):2009-23.
33. Qin T, Zeng Y-d, Qin G, Xu F, Lu J-b, Fang W-f, et al. High PD-L1 expression was associated with poor prognosis in 870 Chinese patients with breast cancer. Oncotarget. 2015;6(32):33972.
34. Lin Y-M, Sung W-W, Hsieh M-J, Tsai S-C, Lai H-W, Yang S-M, et al. High PD-L1 expression correlates with metastasis and poor prognosis in oral squamous cell carcinoma. PloS one. 2015;10(11):e0142656.
35. Taghiloo S, Allahmoradi E, Ebadi R, Tehrani M, Hosseini-Khah Z, Janbabaei G, et al. Upregulation of Galectin-9 and PD-L1 immune checkpoints molecules in patients with chronic lymphocytic leukemia. Asian Pac J Cancer Prev. 2017;18(8):2269.
36. Taghiloo S, Allahmoradi E, Tehrani M, Hossein‐Nataj H, Shekarriz R, Janbabaei G, et al. Frequency and functional characterization of exhausted CD 8+ T cells in chronic lymphocytic leukemia. Eur J Haematol. 2017;98(6):622-31.
37. Allahmoradi E, Taghiloo S, Tehrani M, Hossein-Nattaj H, Janbabaei G, Shekarriz R, et al. CD4+ T cells are exhausted and show functional defects in chronic lymphocytic leukemia. Iran J Immunol. 2017;14(4):257-69.
38. Silva IG, Yasinska IM, Sakhnevych SS, Fiedler W, Wellbrock J, Bardelli M, et al. The Tim-3-galectin-9 secretory pathway is involved in the immune escape of human acute myeloid leukemia cells. EBioMedicine. 2017;22(5):44-57.
39. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252.
40. Zhao L, Li C, Liu F, Zhao Y, Liu J, Hua Y, et al. A blockade of PD-L1 produced antitumor and antimetastatic effects in an orthotopic mouse pancreatic cancer model via the PI3K/Akt/mTOR signaling pathway. Onco Targets Ther. 2017;10:2115.
41. Folgiero V, Cifaldi L, Pira GL, Goffredo BM, Vinti L, Locatelli F. TIM-3/Gal-9 interaction induces IFNγ-dependent IDO1 expression in acute myeloid leukemia blast cells. J Hematol Oncol. 2015;8(1):36.
42. Ritprajak P, Azuma M. Intrinsic and extrinsic control of expression of the immunoregulatory molecule PD-L1 in epithelial cells and squamous cell carcinoma. Oral Oncol. 2015;51(3):221-8.
43. Lastwika KJ, Wilson W, Li QK, Norris J, Xu H, Ghazarian SR, et al. Control of PD-L1 expression by oncogenic activation of the AKT–mTOR pathway in non–small cell lung cancer. Cancer Res. 2016;76(2):227-38.
44. Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007;13(1):84.
45. Zhang X, Zeng Y, Qu Q, Zhu J, Liu Z, Ning W, et al. PD-L1 induced by IFN-γ from tumor-associated macrophages via the JAK/STAT3 and PI3K/AKT signaling pathways promoted progression of lung cancer. Int J Clin Oncol. 2017;22(6):1026-33.
46. Zhang Y, Zhang J, Xu K, Xiao Z, Sun J, Xu J, et al. PTEN/PI3K/mTOR/B7-H1 signaling pathway regulates cell progression and immuno-resistance in pancreatic cancer. Hepatogastroenterology. 2013;60(127):1766-72.
47. Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D, et al. Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-γ and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood. 2007;110(1):296-304.
2. Saultz J, Garzon R. Acute myeloid leukemia: a concise review. J Clin Med. 2016;5(3):33.
3. Deng L, Jiang L, Lin X-h, Tseng K-F, Liu Y, Zhang X, et al. The PI3K/mTOR dual inhibitor BEZ235 suppresses proliferation and migration and reverses multidrug resistance in acute myeloid leukemia. Acta Pharmacol Sin. 2017;38(3):382.
4. Feldman EJ. Novel therapeutics for therapy-related acute myeloid leukemia: 2014. Clin Lymphoma Myeloma Leuk. 2015;15:S91-S3.
5. Sandhöfer N, Metzeler K, Rothenberg M, Herold T, Tiedt S, Groiss V, et al. Dual PI3K/mTOR inhibition shows antileukemic activity in MLL-rearranged acute myeloid leukemia. Leukemia. 2015;29(4):828-38.
6. Khaled S, Monzr Al Malki M, Marcucci G. Acute myeloid leukemia: biologic, prognostic, and therapeutic insights. Oncology. 2016;30(4).
7. Bertacchini J, Heidari N, Mediani L, Capitani S, Shahjahani M, Ahmadzadeh A, et al. Targeting PI3K/AKT/mTOR network for treatment of leukemia. Cell Mol Life Sci. 2015;72(12):2337-47.
8. Brenner A, Andersson Tvedt T, Bruserud Ø. The complexity of targeting PI3K-Akt-mTOR signalling in human acute myeloid leukaemia: the importance of leukemic cell heterogeneity, neighbouring mesenchymal stem cells and immunocompetent cells. Molecules. 2016;21(11):1512.
9. Polak R, Buitenhuis M. The PI3K/PKB signaling module as key regulator of hematopoiesis: implications for therapeutic strategies in leukemia. Blood. 2012;119(4):911-23.
10. Nepstad I, Reikvam H, Brenner A, Bruserud Ø, Hatfield K. Resistance to the antiproliferative in vitro effect of PI3K-Akt-mTOR inhibition in primary human acute myeloid leukemia cells is associated with altered cell metabolism. Int Mol Sci. 2018;19(2):382.
11. Brotelle T, Bay J-O. PI3K-AKT-mTOR pathway: Description, therapeutic development, resistance, predictive/prognostic biomarkers and therapeutic applications for cancer. Bull Cancer. 2016;103(1):18-29.
12. Dos Santos C, Récher C, Demur C, Payrastre B. The PI3K/Akt/mTOR pathway: a new therapeutic target in the treatment of acute myeloid leukemia. Bull Cancer. 2006;93(5):445-7.
13. Smyth MJ, Dunn GP, Schreiber RD. Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol. 2006;90:1-50.
14. A Knaus H, G Kanakry C, Luznik L, Gojo I. Immunomodulatory drugs: immune checkpoint agents in acute leukemia. Curr Drug Targets. 2017;18(3):315-31.
15. Jiang X, Wang J, Deng X, Xiong F, Ge J, Xiang B, et al. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol Cancer. 2019;18(1):10.
16. Taghiloo S, Asgarian-Omran H. Immune evasion mechanisms in Acute Myeloid Leukemia; a focus on immune checkpoint pathways. Crit Rev Oncol Hematol. 2020:103164.
17. Teague RM, Kline J. Immune evasion in acute myeloid leukemia: current concepts and future directions. J Immunother Cancer. 2013;1(1):13.
18. Rajabian Z, Kalani F, Taghiloo S, Tehrani M, Rafiei A, Hosseini-Khah Z, et al. Over-expression of immunosuppressive molecules, PD-L1 and PD-L2, in ulcerative colitis patients. Iran J Immunol. 2019;16(1):62-70.
19. 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.
20. Beatty GL, Gladney WL. Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res. 2015;21(4):687-92.
21. Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol Immunother. 2005;54(4):307-14.
22. Drake CG, Jaffee E, Pardoll DM. Mechanisms of immune evasion by tumors. Adv Immunol. 2006;90:51-81.
23. Peng S, Wang R, Zhang X, Ma Y, Zhong L, Li K, et al. EGFR-TKI resistance promotes immune escape in lung cancer via increased PD-L1 expression. Mol. Cancer. 2019;18(1):165.
24. Dong L, Lv H, Li W, Song Z, Li L, Zhou S, et al. Co-expression of PD-L1 and p-AKT is associated with poor prognosis in diffuse large B-cell lymphoma via PD-1/PD-L1 axis activating intracellular AKT/mTOR pathway in tumor cells. Oncotarget. 2016;7(22):33350.
25. Barrett D, Brown VI, Grupp SA, Teachey DT. Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies. Paediatr Drugs. 2012;14(5):299-316.
26. Herschbein L, Liesveld JL. Dueling for dual inhibition: Means to enhance effectiveness of PI3K/Akt/mTOR inhibitors in AML. Blood Rev. 2018;32(3):235-48.
27. Martelli AM, Evangelisti C, Chiarini F, McCubrey JA. The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients. Oncotarget. 2010;1(2):89.
28. Park S, Chapuis N, Tamburini J, Bardet V, Cornillet-Lefebvre P, Willems L, et al. Role of the PI3K/AKT and mTOR signaling pathways in acute myeloid leukemia. haematologica. 2010;95(5):819-28.
29. Lang F, Wunderle L, Badura S, Schleyer E, Brüggemann M, Serve H, et al. A phase I study of a dual PI3-kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia. BMC pharmacol. 2020;21(1):1-14.
30. Chapuis N, Tamburini J, Green AS, Vignon C, Bardet V, Neyret A, et al. Dual inhibition of PI3K and mTORC1/2 signaling by NVP-BEZ235 as a new therapeutic strategy for acute myeloid leukemia. Clin Cancer Res. 2010;16(22):5424-35.
31. Hao Y, Zhang N, Wei N, Yin H, Zhang Y, Xu H, et al. Matrine induces apoptosis in acute myeloid leukemia cells by inhibiting the PI3K/Akt/mTOR signaling pathway. Oncol. Lett. 2019;18(3):2891-6.
32. Martelli AM, Tazzari P, Evangelisti C, Chiarini F, Blalock W, Billi A, et al. Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin module for acute myelogenous leukemia therapy: from bench to bedside. Curr Med Chem. 2007;14(19):2009-23.
33. Qin T, Zeng Y-d, Qin G, Xu F, Lu J-b, Fang W-f, et al. High PD-L1 expression was associated with poor prognosis in 870 Chinese patients with breast cancer. Oncotarget. 2015;6(32):33972.
34. Lin Y-M, Sung W-W, Hsieh M-J, Tsai S-C, Lai H-W, Yang S-M, et al. High PD-L1 expression correlates with metastasis and poor prognosis in oral squamous cell carcinoma. PloS one. 2015;10(11):e0142656.
35. Taghiloo S, Allahmoradi E, Ebadi R, Tehrani M, Hosseini-Khah Z, Janbabaei G, et al. Upregulation of Galectin-9 and PD-L1 immune checkpoints molecules in patients with chronic lymphocytic leukemia. Asian Pac J Cancer Prev. 2017;18(8):2269.
36. Taghiloo S, Allahmoradi E, Tehrani M, Hossein‐Nataj H, Shekarriz R, Janbabaei G, et al. Frequency and functional characterization of exhausted CD 8+ T cells in chronic lymphocytic leukemia. Eur J Haematol. 2017;98(6):622-31.
37. Allahmoradi E, Taghiloo S, Tehrani M, Hossein-Nattaj H, Janbabaei G, Shekarriz R, et al. CD4+ T cells are exhausted and show functional defects in chronic lymphocytic leukemia. Iran J Immunol. 2017;14(4):257-69.
38. Silva IG, Yasinska IM, Sakhnevych SS, Fiedler W, Wellbrock J, Bardelli M, et al. The Tim-3-galectin-9 secretory pathway is involved in the immune escape of human acute myeloid leukemia cells. EBioMedicine. 2017;22(5):44-57.
39. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252.
40. Zhao L, Li C, Liu F, Zhao Y, Liu J, Hua Y, et al. A blockade of PD-L1 produced antitumor and antimetastatic effects in an orthotopic mouse pancreatic cancer model via the PI3K/Akt/mTOR signaling pathway. Onco Targets Ther. 2017;10:2115.
41. Folgiero V, Cifaldi L, Pira GL, Goffredo BM, Vinti L, Locatelli F. TIM-3/Gal-9 interaction induces IFNγ-dependent IDO1 expression in acute myeloid leukemia blast cells. J Hematol Oncol. 2015;8(1):36.
42. Ritprajak P, Azuma M. Intrinsic and extrinsic control of expression of the immunoregulatory molecule PD-L1 in epithelial cells and squamous cell carcinoma. Oral Oncol. 2015;51(3):221-8.
43. Lastwika KJ, Wilson W, Li QK, Norris J, Xu H, Ghazarian SR, et al. Control of PD-L1 expression by oncogenic activation of the AKT–mTOR pathway in non–small cell lung cancer. Cancer Res. 2016;76(2):227-38.
44. Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007;13(1):84.
45. Zhang X, Zeng Y, Qu Q, Zhu J, Liu Z, Ning W, et al. PD-L1 induced by IFN-γ from tumor-associated macrophages via the JAK/STAT3 and PI3K/AKT signaling pathways promoted progression of lung cancer. Int J Clin Oncol. 2017;22(6):1026-33.
46. Zhang Y, Zhang J, Xu K, Xiao Z, Sun J, Xu J, et al. PTEN/PI3K/mTOR/B7-H1 signaling pathway regulates cell progression and immuno-resistance in pancreatic cancer. Hepatogastroenterology. 2013;60(127):1766-72.
47. Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D, et al. Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-γ and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood. 2007;110(1):296-304.
| Files | ||
| Issue | Vol 21 No 2 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v21i2.9225 | |
| Keywords | ||
| Acute myeloid leukemia Everolimus Idelalisib Immune evasion MK 2206 | ||
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How to Cite
1.
Taghiloo S, Norozi S, Asgarian-Omran H. The Effects of PI3K/Akt/mTOR Signaling Pathway Inhibitors on the Expression of Immune Checkpoint Ligands in Acute Myeloid Leukemia Cell Line. Iran J Allergy Asthma Immunol. 2022;21(2):178-188.
