Abstract
Purpose: We aimed to evaluate the expression level of programmed death ligand-1 (PD-L1) and its effects on prognosis in acute myeloid leukemia. Methods: The flow cytometry was used to detect PD-L1 expression on leukemic cells of 86 de novo acute myeloid leukemia patients with longitudinal follow-up. Results: Median follow-up was 13 (0–73) months. The mean of expression level was 3.22 ± 0.47 at diagnosis and ranged from 0 to 28%. PD-L1 expression tended to be lower in patients with acute promyelocytic leukemia (2.47 ± 1.08, p = 0.09) but there was no significant difference between neither diagnostic nor cytogenetic subgroups. There was no difference in PD-L1 levels between the patients who achieved complete remission (3.4 ± 0.61) and those who did not (2.91 ± 0.72, p = 0.94). The patients with low PD-L1 at diagnosis (median 25 mo [95% CI; 0–56.7]) had a longer overall survival compared with high PD-L1 (median 13 mo [95% CI; 5.52–25.17], p = 0.079). PD-L1 expression was lower at relapse (2.04 ± 0.79) compared to initial diagnosis (4.52 ± 0.93, p = 0.049). The patients who had overall survival longer than 1 year showed lower PD-L1 expression at relapse (0.66 ± 0.93) compared with who had not (5.06 ± 4.28, p = 0.052). A negative correlation between CD33 and PD-L1 (r = − 0.303, p = 0.005) was detected. Conclusion: Despite its low expression levels, PD-L1 appears to be a clinically important prognostic factor. The negative correlation determined between PD-L1 and CD33 supports the combination approach of PD-L1 inhibitors and CD33 targeted immunotherapies.
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Shallis RM, Wang R, Davidoff A, Ma X, Zeidan AM (2019) Epidemiology of acute myeloid leukemia: Recent progress and enduring challenges. Blood Rev. https://doi.org/10.1016/j.blre.2019.04.005
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O’Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR (2016) KEYNOTE-024 Investigators. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. https://doi.org/10.1056/NEJMoa1606774
Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD (2018) Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. https://doi.org/10.1016/S1470-2045(18)30700-9
Ramchandren R, Domingo-Domènech E, Rueda A, Trněný M, Feldman TA, Lee HJ, Provencio M, Sillaber C, Cohen JB, Savage KJ, Willenbacher W, Ligon AH, Ouyang J, Redd R, Rodig SJ, Shipp MA, Sacchi M, Sumbul A, Armand P, Ansell SM (2019) Nivolumab for Newly Diagnosed Advanced-Stage Classic Hodgkin Lymphoma: Safety and Efficacy in the Phase II CheckMate 205 Study. J Clin Oncol. https://doi.org/10.1200/JCO.19.00315
Armand P, Engert A, Younes A, Fanale M, Santoro A, Zinzani PL, Timmerman JM, Collins GP, Ramchandren R, Cohen JB, De Boer JP, Kuruvilla J, Savage KJ, Trneny M, Shipp MA, Kato K, Sumbul A, Farsaci B, Ansell SM (2018) Nivolumab for relapsed/refractory classic hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 205 trial. J Clin Oncol. https://doi.org/10.1200/JCO.2017.76.0793
Liao D, Wang M, Liao Y, Li J, Niu T (2019) A review of efficacy and safety of checkpoint ınhibitor for the treatment of acute myeloid leukemia. Front Pharmacol. https://doi.org/10.3389/fphar.2019.00609
Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, Chen L, Pardoll DM, Topalian SL, Anders RA (2014) Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-13-3271
Dong Y, Han Y, Huang Y, Jiang S, Huang Z, Chen R, Yu Z, Yu K, Zhang S (2020) PD-L1 ıs expressed and promotes the expansion of regulatory t cells in acute myeloid leukemia. Front Immunol. https://doi.org/10.3389/fimmu.2020.01710
Chen BJ, Chapuy B, Ouyang J, Sun HH, Roemer MG, Xu ML, Yu H, Fletcher CD, Freeman GJ, Shipp MA, Rodig SJ (2013) PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-13-0855
Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D, Saudemont A, Quesnel B (2007) Plasma cells from multiple myeloma patients express B7–H1 (PD-L1) and increase expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood. https://doi.org/10.1182/blood-2006-10-051482
Berthon C, Driss V, Liu J, Kuranda K, Leleu X, Jouy N, Hetuin D, Quesnel B (2010) In acute myeloid leukemia, B7–H1 (PD-L1) protection of blasts from cytotoxic T cells is induced by TLR ligands and interferon-gamma and can be reversed using MEK inhibitors. Cancer Immunol Immunother. https://doi.org/10.1007/s00262-010-0909-y
Antohe I, Dǎscǎlescu A, Dǎnǎilǎ C, Titieanu A, Zlei M, Ivanov I, Sireteanu A, Pavel M, Cianga P (2020) B7-Positive and B7-Negative acute myeloid leukemias display distinct T cell maturation profiles, ımmune checkpoint receptor expression, and European Leukemia net risk profiles. Front Oncol. https://doi.org/10.3389/fonc.2020.00264
Tamura H, Dan K, Tamada K, Nakamura K, Shioi Y, Hyodo H, Wang SD, Dong H, Chen L, Ogata K (2005) Expression of functional B7–H2 and B7.2 costimulatory molecules and their prognostic implications in de novo acute myeloid leukemia. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-04-2672
Chen X, Liu S, Wang L, Zhang W, Ji Y, Ma X (2008) Clinical significance of B7–H1 (PD-L1) expression in human acute leukemia. Cancer Biol Ther. https://doi.org/10.4161/cbt.7.5.5689
Zhang ZF, Zhang QT, Xin HZ, Gan SL, Ma J, Liu YF, Xie XS, Sun H (2015) Expression of Programmed Death Ligand-1 (PD-L1) in Human Acute Leukemia and Its Clinical Significance. Zhongguo Shi Yan Xue Ye Xue Za Zhi. https://doi.org/10.7534/j.issn.1009-2137.2015.04.004
Schmohl JU, Nuebling T, Wild J, Kroell T, Kanz L, Salih HR, Schmetzer H (2016) Expression of RANK-L and in part of PD-1 on blasts in patients with acute myeloid leukemia correlates with prognosis. Eur J Haematol. https://doi.org/10.1111/ejh.12762
Krupka C, Kufer P, Kischel R, Zugmaier G, Lichtenegger FS, Köhnke T, Vick B, Jeremias I, Metzeler KH, Altmann T, Schneider S, Fiegl M, Spiekermann K, Bauerle PA, Hiddemann W, Riethmüller G, Subklewe M (2016) Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism. Leukemia. https://doi.org/10.1038/leu.2015.214
Yang H, Bueso-Ramos C, DiNardo C, Estecio MR, Davanlou M, Geng QR, Fang Z, Nguyen M, Pierce S, Wei Y, Parmar S, Cortes J, Kantarjian H, Garcia-Manero G (2014) Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia. https://doi.org/10.1038/leu.2013.355
Daver N, Basu S, Garcia-Manero G, Cortes JE, Ravandi F, Jabbour E, Hendrickson S, Brandt M, Pierce S, Gordon T, Pemmaraju N, Andreeff M, Ning J, Kornblau S, Kadia TM, Dinardo CD, Konopleva M, Allison JP, Kantarjian HM, Sharma P (2017) Phase IB/II study of nivolumab in combination with 5-azacytidine (Aza) in patients (pts) with relapsed acute myeloid leukemia (AML). J Clinic Oncol. https://doi.org/10.1200/JCO.2017.35.15_suppl.7026
Daver N, Boddu P, Garcia-Manero G, Yadav SS, Sharma P, Allison J, Kantarjian H (2018) Hypomethylating agents in combination with immune checkpoint inhibitors in acute myeloid leukemia and myelodysplastic syndromes. Leukemia. https://doi.org/10.1038/s41375-018-0070-8
Huang CY, Zha XF, Wen WR (2019) Expression and Clinical Significance of PD-L1 and MicroRNA-138-5p in Patients with Acute Myeloid Leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi. https://doi.org/10.19746/j.cnki.issn.1009-2137.2019.02.010
Chen C, Liang C, Wang S, Chio CL, Zhang Y, Zeng C, Chen S, Wang C, Li Y (2020) Expression patterns of immune checkpoints in acute myeloid leukemia. J Hematol Oncol. https://doi.org/10.1186/s13045-020-00853-x
Brodská B, Otevřelová P, Šálek C, Fuchs O, Gašová Z, Kuželová K (2019) High PD-L1 expression predicts for worse outcome of leukemia patients with concomitant NPM1 and FLT3 mutations. Int J Mol Sci. https://doi.org/10.3390/ijms20112823
Zajac M, Zaleska J, Dolnik A, Bullinger L, Giannopoulos K (2018) Expression of CD274 (PD-L1) is associated with unfavourable recurrent mutations in AML. Br J Haematol. https://doi.org/10.1111/bjh.15040
Williams P, Basu S, Garcia-Manero G, Hourigan CS, Oetjen KA, Cortes JE, Ravandi F, Jabbour EJ, Al-Hamal Z, Konopleva M, Ning J, Xiao L, Hidalgo Lopez J, Kornblau SM, Andreeff M, Flores W, Bueso-Ramos C, Blando J, Galera P, Calvo KR, Al-Atrash G, Allison JP, Kantarjian HM, Sharma P, Daver NG (2019) The distribution of T-cell subsets and the expression of immune checkpoint receptors and ligands in patients with newly diagnosed and relapsed acute myeloid leukemia. Cancer. https://doi.org/10.1002/cncr.31896
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This retrospective chart review study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Human Investigation Committee of University Kocaeli approved this study. Ethics Committee Approval: GOKAEK-2020/12.30.
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Geduk, A., Atesoglu, E.B., Mehtap, O. et al. Programmed Cell Death Ligand 1 Expression Level and Prognostic Significance in Acute Myeloid Leukemia. Indian J Hematol Blood Transfus 38, 464–472 (2022). https://doi.org/10.1007/s12288-021-01473-2
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DOI: https://doi.org/10.1007/s12288-021-01473-2