Document Type : Original Research
Authors
1 Department of Pathology, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru, Karnataka, India
2 Professor and Head of Department of patology , jss hospital mysore
3 Department of Surgical Gastroenterology JSSMC & Hospital, Mysuru- 04, Karnataka, India
Abstract
Background & Objective: Colorectal carcinoma (CRC) is one of the most common cancers worldwide. The interaction of programmed cell death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1) plays an important role by inhibiting the immune mechanism by which cancer cells escape antitumor immunity. Immunotherapy using checkpoint inhibitors is a growing treatment modality in many cancers; one such is anti-PD1/PD-L1. The present study aimed to study the immunohistochemical (IHC) expression of PD-L1 in CRC and evaluate the association of PD-L1 expression in CRC with various known clinicopathological parameters.
Methods: It was a 2-year prospective study and included 34 colectomy specimens diagnosed as colorectal adenocarcinoma. The expression of PD-L1 was evaluated on tumor cells & tumor-infiltrating immune cells (TIICs) and correlated with various clinicopathological parameters.
Results: Immunohistochemical expression of PD-L1 on tumor cells and tumor microenvironment in CRC revealed positivity in 17.65% of cases each. The PD-L1 expression on tumor cells was associated with lymphovascular invasion (LVI) and perineural invasion (PNI) with P- values of 0.012 and 0.005, respectively, while PD-L1 expression on TIICs was associated with tumor budding with P-value 0.022.
Conclusion: IHC expression of PD-L1 on tumor cells and immune cells was associated with some known poor prognostic factors. Since anti-PD1/PD-L1 is used for targeted therapy, it may be beneficial and economically feasible to evaluate PD-L1 in CRC and establish its role as a prognostic factor.
Keywords
Main Subjects
- GLOBOCAN 2020: New Global Cancer Data [Internet]. Uicc.org. [cited 2021 Feb 4]. Available from: https://www.uicc.org/news/globocan-2020-new-global-cancer- data
- Sharma D, Singh G. Clinico-pathological profile of colorectal cancer in first two decades of life: A retrospective analysis from tertiary health center. Indian J Cancer. 2017;54(2):397-400. [DOI:10.4103/ijc.IJC_225_17] [PMID]
- Nagtegaal ID, Arends MJ, Salto-Tellez M, Colorectal adenocarcinoma. WHO Classification of Tumours editorial board editors. WHO Classification of Tumours: Digestive System Tumours,5th Edition. Lyon, France: International Agency for Research on Cancer, 2019. P. 177-180.
- Wang HB, Yao H, Li CS, Liang LX, Zhang Y, Chen YX, et al. Rise of PD-L1 expression during metastasis of colorectal cancer: Implications for immunotherapy. J Dig Dis. 2017;18(10):574-81. [DOI:10.1111/1751-2980.12538] [PMID]
- Lee LH, Cavalcanti MS, Segal NH, Hechtman JF, Weiser MR, Smith JJ, et al. Patterns and prognostic relevance of PD-1 and PD-L1 expression in colorectal carcinoma. Mod Pathol. 2016;29(11):1433-42. [DOI:10.1038/modpathol.2016.139] [PMID]
- Amin MB, Edge SB. AJCC cancer staging manual: springer; 2017. [DOI:10.1007/978-3-319-40618-3_2]
- Ahtiainen M, Wirta EV, Kuopio T, Seppälä T, Rantala J, Mecklin JP et al. Combined prognostic value of CD274 (PD-L1)/PDCDI (PD-1) expression and immune cell infiltration in colorectal cancer as per mismatch repair status. Mod Pathol. 2019;32(6):866-83. [DOI:10.1038/s41379-019-0219-7] [PMID]
- Wu Z, Yang L, Shi L, Song H, Shi P, Yang T, et al. Prognostic Impact of Adenosine Receptor 2 (A2aR) and Programmed Cell Death Ligand 1 (PD-L1) Expression in Colorectal Cancer. Biomed Res Int. 2019:8014627. [DOI:10.1155/2019/8014627] [PMID]
- SJ, Wang LJ, Wang GD, Guo ZY, Wei M, Meng YL, et al. B7-H1 expression is associated with poor prognosis in colorectal carcinoma and regulates the proliferation and invasion of HCT116 colorectal cancer cells. PLoS One. 2013;8(10):e76012. [DOI:10.1371/journal.pone.0076012] [PMID]
- Yamano T, Yamauchi S, Kimura K, Babaya A, Hamanaka M, Kobayashi M, et al. Japanese Study Group for Postoperative Follow-up of Colorectal Cancer. Influence of age and comorbidity on prognosis and application of adjuvant chemotherapy in elderly Japanese patients with colorectal cancer: A retrospective multicentre study. Eur J Cancer. 2017;81:90-101. [DOI:10.1016/j.ejca.2017.05.024] [PMID]
- Dai W, Li Y, Meng X, Cai S, Li Q, Cai G. Does tumor size have its prognostic role in colorectal cancer? Re-evaluating its value in colorectal adenocarcinoma with different macroscopic growth pattern. Int J Surg. 2017;45:105-12. [DOI:10.1016/j.ijsu.2017.07.100] [PMID]
- Shan T, Chen S, Wu T, Yang Y, Li S, Chen X. PD-L1 expression in colon cancer and its relationship with clinical prognosis. Int J Clin Exp Pathol. 2019;12(5):1764-9.
- 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;29(9):1104-12. [DOI:10.1038/modpathol.2016.95] [PMID]
- Masugi Y, Nishihara R, Yang J, Mima K, da Silva A, Shi Y, et al. Tumour CD274 (PD-L1) expression and T cells in colorectal cancer. Gut. 2017 Aug;66(8):1463-73. [DOI:10.1136/gutjnl-2016-311421] [PMID]
- Schmuck R, Gerken M, Teegen EM, Krebs I, Klinkhammer-Schalke M, Aigner F, et al. Gender comparison of clinical, histopathological, therapeutic and outcome factors in 185,967 colon cancer patients. Langenbecks Arch Surg. 2020;405(1):71-80. [DOI:10.1007/s00423-019-01850-6] [PMID]
- Zhu H, Qin H, Huang Z, Li S, Zhu X, He J et al. Clinical significance of programmed death ligand-1 (PD-L1) in colorectal serrated adenocarcinoma. Int J Clin Exp Pathol. 2015;8(8):9351-9.
- Al-hayali ZW, Mahmood AM, Yahiya ZO, Taib Al--Nuaimy WM. Correlation between programmed cell death ligand1 (PD-L1) expression and clinical parameters in colorectal carcinoma. J Contem Med Sci. 2020;6(4). [DOI:10.22317/jcms.v6i4.810]
- Enkhbat T, Nishi M, Takasu C, Yoshikawa K, Jun H, Tokunaga T et al. Programmed Cell Death Ligand 1 Expression Is an Independent Prognostic Factor in Colorectal Cancer. Anticancer Res. 2018;38(6):3367-73. [DOI:10.21873/anticanres.12603] [PMID]
- 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. [DOI:10.1016/j.ejca.2013.02.015] [PMID]
- Wang L, Ren F, Wang Q, Baldridge LA, Monn MF, Fisher KW, et al. Significance of Programmed Death Ligand 1 (PD-L1) Immunohistochemical Expression in ColorectalCancer. Mol Diagn Ther. 2016;20(2):175-81. [DOI:10.1007/s40291-016-0188-1] [PMID]
- Lee KS, Kim BH, Oh HK, Kim DW, Kang SB, Kim H, et al. Programmed cell death ligand-1 protein expression and CD274/PD-L1 gene amplification in colorectal cancer: Implications for prognosis. Cancer Sci. 2018;109(9):2957-69. [DOI:10.1111/cas.13716] [PMID]
- Stintzing S, Tejpar S, Gibbs P, Thiebach L, Lenz HJ. Understanding the role of primary tumour localisation in colorectal cancer treatment and outcomes. Eur J Cancer. 2017;84:69-80. [DOI:10.1016/j.ejca.2017.07.016] [PMID]
- Jiang H, Zhang R, Jiang H, Zhang M, Guo W, Zhang J, et al. Retrospective analysis of the prognostic value of PD-L1 expression and 18F-FDG PET/CT metabolic parameters in colorectal cancer. J Cancer. 2020;11(10):2864-73. [DOI:10.7150/jca.38689] [PMID]
- Huang CY, Chiang SF, Ke TW, Chen TW, You YS, Chen WT, et al. Clinical significance of programmed death 1 ligand-1 (CD274/PD-L1) and intra-tumoral CD8+ T-cell infiltration in stage II-III colorectal cancer. Sci Rep. 2018;8(1):15658. [DOI:10.1038/s41598-018-33927-5] [PMID]
- Koelzer VH, Lugli A. The tumor border configuration of colorectal cancer as a histomorphological prognostic indicator. Front Oncol. 2014;4:29. [DOI:10.3389/fonc.2014.00029]
- Kim JH, Park HE, Cho NY, Lee HS, Kang GH. Characterisation of PD-L1-positive subsets of microsatellite-unstable colorectal cancers. Br J Cancer. 2016;115(4):490-6. [DOI:10.1038/bjc.2016.211] [PMID]
- Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11(11):3887-95. [DOI:10.1002/j.1460-2075.1992.tb05481.x] [PMID]
- Hansen JD, Du Pasquier L, Lefranc MP, Lopez V, Benmansour A, Boudinot P. The B7 family of immunoregulatory receptors: a comparative and evolutionary perspective. Mol Immunol. 2009;46(3):457-72. [DOI:10.1016/j.molimm.2008.10.007] [PMID]
- Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999; 5(12):1365-9. [DOI:10.1038/70932] [PMID]
- Carter L, Fouser LA, Jussif J, Fitz L, Deng B, Wood CR, et al. PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2. Eur J Immunol. 2002;32(3):634-43. [DOI:10.1002/1521-4141(200203)32:33.0.CO;2-9] [PMID]
- Washington MK. Colorectal carcinoma: selected issues in pathologic examination and staging and determination of prognostic factors. Arch Pathol Lab Med.2008;132(10):1600-7. [DOI:10.5858/2008-132-1600-CCSIIP] [PMID]
- Ogino S, Nosho K, Irahara N, Meyerhardt JA, Baba Y, Shima K, et al. Lymphocytic reaction to colorectal cancer is associated with longer survival, independent of lymph node count, microsatellite instability, and CpG island methylator phenotype. Clin Cancer Res. 2009;15(20):6412-20. [DOI:10.1158/1078-0432.CCR-09-1438] [PMID]
- Shen Z, Gu L, Mao D, Chen M, Jin R. Clinicopathological and prognostic significance of PD-L1 expression in colorectal cancer: a systematic review and meta-analysis. World J Surg Oncol. 2019;17(1):4. [DOI:10.1186/s12957-018-1544-x] [PMID]
- Li Y, He M, Zhou Y, Yang C, Wei S, Bian X, et al. The Prognostic and Clinicopathological Roles of PD-L1 Expression in Colorectal Cancer: A Systematic Review and Meta-Analysis. Front Pharmacol. 2019;10:139. [DOI:10.3389/fphar.2019.00139] [PMID]
- Wang S, Yuan B, Wang Y, Li M, Liu X, Cao J et al. Clinicopathological and prognostic significance of PD-L1 expression in colorectal cancer: a meta-analysis. Int J Colorectal Dis. 2021;36(1):117-30. [DOI:10.1007/s00384-020-03734-4] [PMID]
)