Expressions of PD-L1 and A2aR in colorectal cancer and its clinical significances_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YANG Lin ^1,2 , SHI Linsen ^1,3 , JIANG Tao ^1,3 , WU Zhaoying ^1,2 ,  SONG Jun ^1,3

1. Department of Gastrointestinal Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, P. R. China;
2. Graduate School of Xuzhou Medical University, Xuzhou, Jiangsu 221002, P. R. China;
3. Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, Jiangsu 221002, P. R. China;

Corresponding author：

SONG Jun, Email: songjunwk@126.com

Keywords：

colorectal cancer; cell programmed death ligand 1; adenosine 2a receptor

DOI：

10.7507/1007-9424.201811025

Video：

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Objective To detect expressions of cell programmed death ligand 1 (PD-L1) and adenosine 2a receptor (A2aR) proteins in colorectal cancer tissues and investigate its relationship with clinicopathologic features of patients with colorectal cancer.Methods The colorectal cancer tissues and corresponding paracancerous tissues of 106 patients with colorectal cancer were collected, the patients underwent surgery in the Affiliated Hospital of Xuzhou Medical University from August 2013 to August 2015. The immunohistochemical staining was used to detect the expressions of A2aR and PD-L1 proteins.Results The positive rates of A2aR and PD-L1 protein expression in the colorectal cancer tissues were significantly higher than those in the corresponding paracancerous tissues, respectively [A2aR: 74 (69.8%) versus 35 (33.0%), χ²=28.721, P<0.001; PD-L1: 57 (53.8%) versus 28 (26.4%), χ²=16.516, P<0.001], which in the colorectal cancer tissues were correlated with the Broders grading (A2aR: χ²=9.198, P=0.010; PD-L1: χ²=8.354, P=0.015), T staging (A2aR: χ²=6.737, P=0.009; PD-L1: χ²=6.437, P=0.011), and TNM staging (A2aR: χ²=4.884, P=0.027; PD-L1: χ²=8.246, P=0.004) and were not correlated with the gender, age, tumor portion, lymph node metastasis and CA19-9 (P>0.05), but the positive rates of A2aR protein expression were correlated with the tumor diameter (χ²=4.386, P=0.036) and CEA positive (χ²=6.315, P=0.012), and the positive rates of PD-L1 protein expression were not correlated with them (P>0.05). The expression of PD-L1 protein was positively correlated with the expression of A2aR in the colorectal cancer tissues (r_s=0.237, P=0.027).Conclusion PD-L1 and A2aR protein expressions are higher in colorectal cancer tissues, it is provided that both of them might play an important role in promoting occurrence and development of colorectal cancer.

Citation： YANG Lin, SHI Linsen, JIANG Tao, WU Zhaoying, SONG Jun. Expressions of PD-L1 and A2aR in colorectal cancer and its clinical significances. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2019, 26(4): 423-427. doi: 10.7507/1007-9424.201811025 Copy

1.	Mahoney KM, Rennert PD, Freeman GJ. Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov, 2015, 14(8): 561-584.
2.	Bertucci F, Finetti P, Colpaert C, et al. PDL1 expression in inflammatory breast cancer is frequent and predicts for the pathological response to chemotherapy. Oncotarget, 2015, 6(15): 13506-13519.
3.	Tkachev V, Goodell S, Opipari AW, et al. Programmed death-1 controls T cell survival by regulating oxidative metabolism. J Immunol, 2015, 194(12): 5789-5800.
4.	Leone RD, Lo YC, Powell JD. A2aR antagonists: Next generation checkpoint blockade for cancer immunotherapy. Comput Struct Biotechnol J, 2015, 13: 265-272.
5.	Hatfield SM, Sitkovsky M. A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1α driven immunosuppression and improve immunotherapies of cancer. Curr Opin Pharmacol, 2016, 29: 90-96.
6.	柴立勋, 孙克林, 郭黎平. 食管鳞癌中 Ezrin 和 CD44-v6 的表达及其临床意义. 中华肿瘤杂志, 2007, 29(9): 685-688.
7.	Mu CY, Huang JA, Chen Y, et al. High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation. Med Oncol, 2011, 28(3): 682-688.
8.	Dong HD, Zhu GF, Tamada K, et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med, 1999, 5(12): 1365-1369.
9.	吕学文, 徐琼, 陈焕伟, 等. PD-1、PD-L1 蛋白在外周 T 细胞淋巴瘤中的表达及其与预后的关系. 肿瘤药学, 2016, 6(1): 44-48.
10.	Lizée G, Overwijk WW, Radvanyi L, et al. Harnessing the power of the immune system to target cancer. Annu Rev Med, 2013, 64: 71-90.
11.	Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med, 2015, 373(19): 1803-1813.
12.	Zuo QZ, Qin WX. Progress of CTLA-4 and PD-1 signaling pathways in immunotherapy for human solid cancers. Chin Bull Life Sci, 2017, 29(8): 713-720.
13.	Sun Z, Fourcade J, Pagliano O, et al. IL10 and PD-1 cooperate to limit the activity of tumor-specific CD8⁺ T cells. Cancer Res, 2015, 75(8): 1635-1644.
14.	Pyo JS, Kang G, Kim JY. Prognostic role of PD-L1 in malignant solid tumors: a meta-analysis. Int J Biol Markers, 2017, 32(1): e68-e74.
15.	Uruga H, Bozkurtlar E, Huynh TG, et al. Programmed cell death ligand (PD-L1) expression in stage Ⅱ and Ⅲ lung adenocarcinomas and nodal metastases. J Thorac Oncol, 2017, 12(3): 458-466.
16.	韩丽娟, 李汝平, 陈新峰, 等. B7 家族及其受体 PD-1 在人 NK/T 细胞淋巴瘤中的表达及临床意义. 中国肿瘤临床, 2014, 41(6): 363-367.
17.	Müller CE, Jacobson KA. Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim Biophys Acta, 2011, 1808(5): 1290-1308.
18.	Yuan G, Jones GB. Towards next generation adenosine A(2A) receptor antagonists. Curr Med Chem, 2014, 21(34): 3918-3935.
19.	Whiteside TL, Mandapathil M, Schuler P. The role of the adeno-sinergic pathway in immunosuppression mediated by human regulatory T cells (Treg). Curr Med Chem, 2011, 18(34): 5217-5223.
20.	Beavis PA, Divisekera U, Paget C, et al. Blockade of A2A receptors potently suppresses the metastasis of CD73⁺ tumors. Proc Natl Acad Sci U S A, 2013, 110(36): 14711-14716.
21.	Cekic C, Day YJ, Sag D, et al. Myeloid expression of adenosine A2A receptor suppresses T and NK cell responses in the solid tumor microenvironment. Cancer Res, 2014, 74(24): 7250-7259.
22.	Young A, Ngiow SF, Barkauskas DS, et al. Co-inhibition of CD73 and A2AR adenosine signaling improves anti-tumor immune responses. Cancer Cell, 2016, 30(3): 391-403.
23.	Beavis PA, Milenkovski N, Henderson MA, et al. Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced antitumor T-cell responses. Cancer Immunol Res, 2015, 3(5): 506-517.

1. Mahoney KM, Rennert PD, Freeman GJ. Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov, 2015, 14(8): 561-584.
2. Bertucci F, Finetti P, Colpaert C, et al. PDL1 expression in inflammatory breast cancer is frequent and predicts for the pathological response to chemotherapy. Oncotarget, 2015, 6(15): 13506-13519.
3. Tkachev V, Goodell S, Opipari AW, et al. Programmed death-1 controls T cell survival by regulating oxidative metabolism. J Immunol, 2015, 194(12): 5789-5800.
4. Leone RD, Lo YC, Powell JD. A2aR antagonists: Next generation checkpoint blockade for cancer immunotherapy. Comput Struct Biotechnol J, 2015, 13: 265-272.
5. Hatfield SM, Sitkovsky M. A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1α driven immunosuppression and improve immunotherapies of cancer. Curr Opin Pharmacol, 2016, 29: 90-96.
6. 柴立勋, 孙克林, 郭黎平. 食管鳞癌中 Ezrin 和 CD44-v6 的表达及其临床意义. 中华肿瘤杂志, 2007, 29(9): 685-688.
7. Mu CY, Huang JA, Chen Y, et al. High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation. Med Oncol, 2011, 28(3): 682-688.
8. Dong HD, Zhu GF, Tamada K, et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med, 1999, 5(12): 1365-1369.
9. 吕学文, 徐琼, 陈焕伟, 等. PD-1、PD-L1 蛋白在外周 T 细胞淋巴瘤中的表达及其与预后的关系. 肿瘤药学, 2016, 6(1): 44-48.
10. Lizée G, Overwijk WW, Radvanyi L, et al. Harnessing the power of the immune system to target cancer. Annu Rev Med, 2013, 64: 71-90.
11. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med, 2015, 373(19): 1803-1813.
12. Zuo QZ, Qin WX. Progress of CTLA-4 and PD-1 signaling pathways in immunotherapy for human solid cancers. Chin Bull Life Sci, 2017, 29(8): 713-720.
13. Sun Z, Fourcade J, Pagliano O, et al. IL10 and PD-1 cooperate to limit the activity of tumor-specific CD8⁺ T cells. Cancer Res, 2015, 75(8): 1635-1644.
14. Pyo JS, Kang G, Kim JY. Prognostic role of PD-L1 in malignant solid tumors: a meta-analysis. Int J Biol Markers, 2017, 32(1): e68-e74.
15. Uruga H, Bozkurtlar E, Huynh TG, et al. Programmed cell death ligand (PD-L1) expression in stage Ⅱ and Ⅲ lung adenocarcinomas and nodal metastases. J Thorac Oncol, 2017, 12(3): 458-466.
16. 韩丽娟, 李汝平, 陈新峰, 等. B7 家族及其受体 PD-1 在人 NK/T 细胞淋巴瘤中的表达及临床意义. 中国肿瘤临床, 2014, 41(6): 363-367.
17. Müller CE, Jacobson KA. Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim Biophys Acta, 2011, 1808(5): 1290-1308.
18. Yuan G, Jones GB. Towards next generation adenosine A(2A) receptor antagonists. Curr Med Chem, 2014, 21(34): 3918-3935.
19. Whiteside TL, Mandapathil M, Schuler P. The role of the adeno-sinergic pathway in immunosuppression mediated by human regulatory T cells (Treg). Curr Med Chem, 2011, 18(34): 5217-5223.
20. Beavis PA, Divisekera U, Paget C, et al. Blockade of A2A receptors potently suppresses the metastasis of CD73⁺ tumors. Proc Natl Acad Sci U S A, 2013, 110(36): 14711-14716.
21. Cekic C, Day YJ, Sag D, et al. Myeloid expression of adenosine A2A receptor suppresses T and NK cell responses in the solid tumor microenvironment. Cancer Res, 2014, 74(24): 7250-7259.
22. Young A, Ngiow SF, Barkauskas DS, et al. Co-inhibition of CD73 and A2AR adenosine signaling improves anti-tumor immune responses. Cancer Cell, 2016, 30(3): 391-403.
23. Beavis PA, Milenkovski N, Henderson MA, et al. Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced antitumor T-cell responses. Cancer Immunol Res, 2015, 3(5): 506-517.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Expressions of PD-L1 and A2aR in colorectal cancer and its clinical significances

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