The mRNA Expression Profile of PD-1 and PD-L1 in Peripheral Blood of Colorectal Cancer Patients

Ajoedi Ajoedi* -  Digestive Surgery Department, National Cancer Center-Dharmais Cancer Hospital, Jakarta, Indonesia
Muhammad Al Azhar -  Research and Development Department, Dharmais Hospital-National Cancer Center, Jakarta, Indonesia, Indonesia
Siti Nadliroh -  Research and Development Department, Dharmais Hospital-National Cancer Center, Jakarta, Indonesia
Sri Hartini -  Clinical Pathology Department, Dharmais Hospital-National Cancer Center, Jakarta, Indonesia
Rizka Andalusia -  Research and Development Department, Dharmais Hospital-National Cancer Center, Jakarta, Indonesia
Arief Budi Witarto -  Faculty of Biotechnology, Sumbawa University of Technology, West Nusa Tenggara, Indonesia

DOI : 10.33371/ijoc.v13i3.670

Background: Immunotherapy using immune checkpoint inhibitors has currently emerged as an effective treatment for a subset of colorectal cancer (CRC) patients. The roles of PD-1 and PD-L1 expression levels in peripheral blood to predict patient’s response to immune checkpoint inhibitors are not well established. Therefore, we analyzed PD-1 and PD-L1 mRNA expression levels of peripheral blood in Indonesian CRC patients and explored the association with the clinicopathological features.

Methods: Peripheral blood of 25 CRC patients and 10 healthy individuals were collected in Dharmais Hospital-National Cancer Center from 2017 to 2018. PD-1 and PD-L1 mRNA expression levels were analyzed using real time PCR. The associations with clinicopathological variables were analyzed with fisher-exact test or chi square test.

Results: PD-1 mRNA expression levels were significantly lower in CRC patients compared to healthy individuals (HI) (mean: 0.0015 ± 0.0013 and 0.017 ± 0.010 respectively, p < 0.001). Although PD-L1 mRNA expression levels were lower in CRC patients, the difference was not statistically significant (mean in CRC and HI: 0.021 ± 0.013 and 0.034 ± 0.028 respectively, p = 0.125). The expression of PD-L1 was higher in CRC females compared to males (p = 0.03). The expression levels of PD-L1 were not associated with different ages (p = 0.673), stages (p = 0.298), histological type of colorectal cancer (p=0.852), patient status (p = 1.000), and body mass index (p = 0.514).

Conclusions: The mRNA expression levels of PD-1 and PD-L1 were lower in CRC patients compared to healthy controls. Expression of PD-L1 were correlated with sex, but not correlated with ages, stages, histological type of CRC, patient status, and body mass index.

Keywords
colorectal cancer, immunotherapy, PD-1, PD-L1
  1. International Agency of Research on Cancer (IARC). Latest global cancer data : Cancer burden rises to 18.1 million new cases and 9.6 million cancer deaths in 2018 [Internet]. Geneva: IARC; 12 Sep 2018 [cited 2019 April 15]. Available from: https://www.who.int/cancer/PRGlobocanFinal.pdf
  2. DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, et al. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin. 2014;64(4):252–71.
  3. Augestad KM, Merok MA, Ignatovic D. Tailored treatment of colorectal cancer: Surgical, molecular, and genetic considerations. Clin Med Insights Oncol. 2017;11.
  4. Topalian SL, Taube JM, Anders RA, Pardoll DM. in cancer therapy. Nat Publ Gr. 2016;16(5):275–87.
  5. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and Its Ligands in Tolerance and Immunity. Annu Rev Immunol. 2008;26(1):677–704.
  6. Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009;206(13):3015–29.
  7. He J, Hu Y, Hu M, Li B. Development of PD-1 / PD-L1 Pathway in Tumor Immune Microenvironment and Treatment for Non-Small Cell Lung Cancer. Nat Publ Gr. 2015;(July):1–9.
  8. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Publ Gr [Internet]. 2012;12(4):252–64. Available from: http://dx.doi.org/10.1038/nrc3239.
  9. Valentini AM, Pinto F Di, Cariola F, Guerra V, Caruso ML, Pirrelli M. PD-L1 expression in colorectal cancer defines three subsets of tumor immune microenvironments. 2018;9(9):8584–96.
  10. Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, et al. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer. 2010;116(7):1757–66.
  11. Wu P, Wu D, Li L, Chai Y, Huang J. PD-L1 and survival in solid tumors: A meta-analysis. PLoS One. 2015;10(6):1–15.
  12. Amatatsu M, Arigami T, Uenosono Y, Yanagita S, Uchikado Y, Kijima Y, et al. Programmed death-ligand 1 is a promising blood marker for predicting tumor progression and prognosis in patients with gastric cancer. Cancer Sci. 2018;109(3):814–20.
  13. Wang W, Shen G, Wu S, Song S, Ni Y, Suo Z, et al. PD-1 mRNA expression in peripheral blood cells and its modulation characteristics in cancer patients. Oncotarget. 2017;8(31):50782–91.
  14. MacFarlane AW, Jillab M, Plimack ER, Hudes GR, Uzzo RG, Litwin S, et al. PD-1 Expression on Peripheral Blood Cells Increases with Stage in Renal Cell Carcinoma Patients and Is Rapidly Reduced after Surgical Tumor Resection. Cancer Immunol Res. 2013;2(4):320–31.
  15. Waki K, Yamada T, Yoshiyama K, Terazaki Y, Sakamoto S, Matsueda S, et al. PD-1 expression on peripheral blood T-cell subsets correlates with prognosis in non-small cell lung cancer. Cancer Sci. 2014;105(10):1229–35.
  16. Song M, Chen D, Lu B, Wang C, Zhang J, Huang L, et al. PTEN Loss Increases PD-L1 Protein Expression and Affects the Correlation between PD-L1 Expression and Clinical Parameters in Colorectal Cancer. PLoS One. 2013;8(6).
  17. Droeser RA, Hirt C, Viehl CT, Frey DM, Nebiker C, Huber X, et al. Clinical impact of programmed cell death ligand 1 expression in colorectal cancer. Eur J Cancer. 2013;49(9):2233–42.
  18. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods. 2001;25(4):402–8.
  19. Gasser M, Grimm M, Nichiporuk E, Bueter M, Lutz J, Lebedeva T, et al. PD-1/PD-L1 expression in colorectal cancer and its implications for apoptosis and tumor immune evasion. Cancer Res. 2006;66(8 Supplement):1118 LP – 1118.
  20. Lee LH, Cavalcanti MS, Segal NH, Hechtman JF, Martin R. Patterns and prognostic relevance of PD-1 and PD-L1 expression in colorectal carcinoma. Mod Pathol. 2016;29(11):1433–42.
  21. Albitar M, Sudarsanam S, Ma W, Jiang S, Chen W, Funari VA, et al. Expression of PD-L1 in colorectal cancer that lack mutations in RAS or TP53 genes. J Clin Oncol. 2017;35(15_suppl):e14500–e14500.
  22. Rosenbaum MW, Bledsoe JR, Morales-oyarvide V, Huynh TG, Mino-kenudson M. PD-L1 expression in colorectal cancer is associated with microsatellite instability , BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes. Mod Pathol. 2016;1–9.
  23. Zhong J, Chen S, Xu L, Lai J, Liao Z, Zhang T, et al. Lower expression of PD-1 and PD-L1 in peripheral blood from patients with chronic ITP Lower expression of PD-1 and PD-L1 in peripheral blood from patients with chronic ITP. Hematology. 2016;8454.
  24. Hassan SS, Akram M, King EC, Dockrell HM, Cliff JM. PD-1 , PD-L1 and PD-L2 Gene Expression on T- Cells and Natural Killer Cells Declines in Conjunction with a Reduction in PD-1 Protein during the Intensive Phase of Tuberculosis Treatment. PLoS One. 2015;1–15.
  25. Goltz D, Gevensleben H, Dietrich J, Dietrich D. Pd-l1 (CD274) promoter methylation predicts survival in colorectal cancer patients. Oncoimmunology. 2017;6(1):1–4.
  26. Bae SU, Jeong WK, Baek SK, Kim NK, Hwang I. Prognostic impact of programmed cell death ligand 1 expression on long-term oncologic outcomes in colorectal cancer. Oncol Lett. 2018;16(4):5214–22.
  27. Koppel C, Schwellenbach H, Zielinski D, Eckstein S, Martin-Ortega M, D’Arrigo C, et al. Optimization and validation of PD-L1 immunohistochemistry staining protocols using the antibody clone 28-8 on different staining platforms. Mod Pathol. 2018;31(11):1630–44.

Full Text:
Article Info
Submitted: 2019-07-31
Published: 2019-10-16
Section: Research Articles
Article Statistics: 37 31