Background: The activities of programmed cell death 1 (PD-1) and programmed death ligand-1 (PD-L1) have already been identified in various cancers. However, in non-Hodgkinʼs lymphoma (NHL), the prognostic value of PD-1/PD-L1 gene polymorphisms and expression levels remains unclear.
Objectives: The present study aimed to investigate the relationship between the genetic polymorphisms of PD-1/PD-L1 genes and NHL in the Iranian population.
Methods: Four single-nucleotide polymorphisms (SNPs) of PD-1/PD-L1 genes were examined in 134 NHL patients and 134 healthy controls using polymerase chain reaction-restriction fragment length polymorphism. The expression levels of PD-1/PD-L1 genes were analyzed using real-time polymerase chain reaction.
Results: The obtained results of the current study demonstrated that PD-L1 rs2890685 (A>C) SNP (P<0.0001) was significantly associated with the increased risk of NHL. The AA genotype of PD-L1 rs2890685 polymorphism was observed to be more prevalent in the NHL patients, compared to that reported for the healthy controls. There was no significant association between PD-L1 rs4143815, PD-1 rs11568821, and PD-1rs2227981 SNPs with the risk of NHL. Furthermore, the obtained findings showed that the messenger ribonucleic acid transcription levels of both PD-1 and PD-L1 were significantly higher in the NHL patients than those reported for the healthy controls (P<0.001).
Conclusion: According to the results of the current study, there was an association between functional PD-L1 rs2890685 polymorphism and risk of NHL, suggesting that the genetic variant of PD-L1 might be a possible prognostic marker for the prediction of the risk and development of NHL.
- Mahase E. Cancer overtakes CVD to become leading cause of death in high income countries. BMJ. 2019;366:I5368. doi: 10.1136/bmj.l5368. [PubMed: 31481521].
- Salmaninejad A, Valilou SF, Shabgah AG, Aslani S, Alimardani M, Pasdar A, et al. PD‐1/PD‐L1 pathway: Basic biology and role in cancer immunotherapy. J Cell Physiol. 2019;234(10):16824-37. doi: 10.1002/jcp.28358. [PubMed: 30784085].
- Li Y, Li F, Jiang F, Lv X, Zhang R, Lu A, et al. A mini-review for cancer immunotherapy: molecular understanding of PD-1/PD-L1 pathway & translational blockade of immune checkpoints. Intjmolsci. 2016;17(7):1151. doi: 10.3390/ijms17071151. [PubMed: 27438833].
- Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl j med. 2016;375(18):1767-78. doi: 10.1056/NEJMra1514296. [PumMed: 27806234].
- Davis AA, Patel VG. The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors. J Immunother Cancer. 2019;7(1):278. doi: 10.1186/s40425-019-0768-9. [PubMed: 31655605].
- Zak KM, Grudnik P, Magiera K, Dömling A, Dubin G, Holak TA. Structural biology of the immune checkpoint receptor PD-1 and its ligands PD-L1/PD-L2. Structure. 2017;25(8):1163-74. doi: 10.1016/j.str.2017.06.011. [PubMed: 28768162].
- 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. doi: 10.1186/s12943-018-0928-4. [PubMed: 30646912].
- Chacon-Cortes D, Griffiths LR. Methods for extracting genomic DNA from whole blood samples: current perspectives. J Bioreposit Sci Appl Med. 2014;2014(2):1-9.
- Kong EK, Prokunina‐Olsson L, Wong WH, Lau CS, Chan TM, Alarcón‐Riquelme M, et al. A new haplotype of PDCD1 is associated with rheumatoid arthritis in Hong Kong Chinese. Arthritis Rheum. 2005;52(4):1058-62. doi: 10.1002/art.20966. [PubMed: 15818672].
- Lee SH, Lee YA, Woo DH, Song R, Park EK, Ryu MH , et al. Association of the programmed cell death 1 (PDCD1) gene polymorphism with ankylosing spondylitis in the Korean population. Arthritis Res Ther. 2006;8(6):R163. doi: 10.1186/ar2071. [PubMed: 17064404].
- Prokunina L, Castillejo-López C, Öberg F, Gunnarsson I, Berg L, Magnusson V, et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet. 2002;32(4):666-9. doi: 10.1038/ng1020. [PubMed: 12402038].
- Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016;8(328):328rv4-rv4. doi: 10.1126/scitranslmed.aad7118. [PubMed: 26936508].
- Zhou RM, Li Y, Liu JH, Wang N, Huang X, Cao SR, et al. Programmed death-1 ligand-1 gene rs2890658 polymorphism associated with the risk of esophageal squamous cell carcinoma in smokers. Cancer Biomark. 2017;21(1):65-71. doi: 10.3233/CBM-170269. [PubMed: 29060926].
- Hashemi M, Karami S, Sarabandi S, Moazeni-Roodi A, Małecki A, Ghavami S, et al. Association between PD-1 and PD-L1 Polymorphisms and the Risk of Cancer: A Meta-Analysis of Case-Control Studies. Cancers (Basel). 2019;11(8):1150. doi: 10.3390/cancers11081150. [PubMed: 31405171].
- Salmaninejad A, Khoramshahi V, Azani A, Soltaninejad E, Aslani S, Zamani MR, et al. PD-1 and cancer: molecular mechanisms and polymorphisms. Immunogenetics. 2018;70(2):73-86. doi: 10.1007/s00251-017-1015-5. [PubMed: 28642997].
- Yin L, Guo H, Zhao L, Wang J. The programmed death-1 gene polymorphism (PD-1.5 C/T) is associated with non-small cell lung cancer risk in a Chinese Han population. Int J Clin Exp Med. 2014;7(12):5832-6. [PubMed: 25664115].
- Dong W, Gong M, Shi Z, Xiao J, Zhang J, Peng J. Programmed cell death-1 polymorphisms decrease the cancer risk: a meta-analysis involving twelve case-control studies. PloS one. 2016;11(3):e0152448. doi: 10.1371/journal.pone.0152448. [PubMed: 27031235].
- Wang W, Li F, Mao Y, Zhou H, Sun J, Li R, et al. A miR-570 binding site polymorphism in the B7-H1 gene is associated with the risk of gastric adenocarcinoma. Hum Genet. 2013;132(6):641-8. doi: 10.1007/s00439-013-1275-6. [PubMed: 23430453].
- Shi XL, Mancham S, Hansen BE, de Knegt RJ, de Jonge J, van der Laan LJ, et al. Counter-regulation of rejection activity against human liver grafts by donor PD-L1 and recipient PD-1 interaction. J Hepatol. 2016;64(6):1274-82. doi: 10.1016/j.jhep.2016.02.034. [PubMed: 26941095].
- Pizarro C, García‐Díaz DF, Codner E, Salas‐Pérez F, Carrasco E, Pérez‐Bravo F. PD‐L1 gene polymorphisms and low serum level of PD‐L1 protein are associated to type 1 diabetes in Chile. DiabetesMetab Res Rev. 2014;30(8):761-6. doi: 10.1002/dmrr.2552. [PubMed: 24816853].
- Vaddepally RK, Kharel P, Pandey R, Garje R, Chandra AB. Review of indications of FDA-Approved immune checkpoint inhibitors per nccn guidelines with the level of evidence. Cancers (Basel). 2020;12(3):738. doi: 10.3390/cancers12030738. [PubMed: 32245016].
- Nomizo T, Ozasa H, Tsuji T, Funazo T, Yasuda Y, Yoshida H, et al. clinical impact of single nucleotide polymorphism in Pd-L1 on response to nivolumab for advanced non-small-cell lung cancer patients. Sci Rep. 2017;7(1):45124. doi: 10.1038/srep45124. [PubMed: 28332580].
- Wu X, Gu Z, Chen Y, Chen B, Chen W, Weng L, et al. Application of PD-1 blockade in cancer immunotherapy. Comput Struct Biotechnol J. 2019;17:661-74. doi: 10.1016/j.csbj.2019.03.006. [PubMed: 31205619].
- Nakanishi J, Wada Y, Matsumoto K, Azuma M, Kikuchi K, Ueda S. Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother. 2007;56(8):1173-82. doi: 10.1007/s00262-006-0266-z. [PubMed: 17186290].
- Gevensleben H, Dietrich D, Golletz C, Steiner S, Jung M, Thiesler T, et al. The immune checkpoint regulator pd-l1 is highly expressed in aggressive primary prostate cancer. Clin Cancer Res. 2016;22(8):1969-77. doi: 10.1158/1078-0432.CCR-15-2042. [PubMed: 26573597].
- Chen BJ, Dashnamoorthy R, Galera P, Makarenko V, Chang H, Ghosh S, et al. The immune checkpoint molecules PD-1, PD-L1, TIM-3 and LAG-3 in diffuse large B-cell lymphoma. Oncotarget. 2019;10(21):2030-40. doi: 10.18632/oncotarget.26771. [PubMed: 31007846].
- Andorsky DJ, Yamada RE, Said J, Pinkus GS, Betting DJ, Timmerman JM. Programmed death ligand 1 is expressed by non–hodgkin lymphomas and inhibits the activity of tumor-associated T cells. Clin Cancer Res. 2011;17(13):4232-44. doi: 10.1158/1078-0432.CCR-10-2660. [PubMed: 21540239].