ORIGINAL ARTICLE
Lymphocyte-activated gene-3 (LAG3) protein expressed in tumor-infiltrating lymphocytes of colorectal cancer
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1
Department of Emergency Medicine, the First Affiliated Hospital of Nanjing Medical University, China
2
Department of Oncology, Jiangyin Clinical College of Xuzhou Medical University, Jiangyin, China
3
Department of Pathology, Jinling Hospital, China
4
Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
Submission date: 2021-02-07
Final revision date: 2021-09-29
Acceptance date: 2021-11-15
Publication date: 2022-03-08
Pol J Pathol 2021;72(4):324-330
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ABSTRACT
Immunotherapy can reverse tumor immune escape by suppressing immune checkpoints. Lymphocyte activation gene 3 (LAG3) is an important checkpoint and its role in colorectal cancer is not clear. In this study, we investigated LAG3 protein expression and its correlation with clinicopathologic parameters. The expression of LAG3 protein was assessed in 150 surgically resected colorectal cancer tissue samples by immunohistochemistry. The relationship between LAG3 expression and clinicopathological parameters, MSI status and survival was statistically analyzed. LAG3 protein was not expressed in colorectal cancer cells, and was expressed on the tumor-infiltrating lymphocytes (TILs) in 31 out of 150 (20.7%) colorectal cancer samples. Positive expression of LAG3 in TILs is associated with lymph node metastasis (p < 0.001), TNM stage (p = 0.024) and MSI-H (p = 0.035). No significant relationship was found between LAG3 expression and gender, age, tumor location, tumor invasion depth, and differentiation. LAG3 expression is associated with longer overall survival (p = 0.045). Our data show LAG3 expression on TILs in parts of CRC tissue. Positive expression of LAG3 was associated with advanced tumor stage, MSI-H and a poor prognosis. We conclude that LAG3 is an important checkpoint gene in CRC and may be a potential marker for prognosis of CRC.
REFERENCES (32)
1.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019; 69: 7-34.
2.
Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016; 66: 115-132.
3.
Wierz M, Pierson S, Guyonnet L, et al. Dual PD1/LAG3 immune checkpoint blockade limits tumor development in a murine model of chronic lymphocytic leukemia. Blood 2018; 131: 1617-1621.
4.
Loo K, Daud A. Emerging biomarkers as predictors to anti-PD1/PD-L1 therapies in advanced melanoma. Immunotherapy 2016; 8: 775-784.
5.
Bertucci F, Finetti P, Birnbaum D, et al. The PD1/PDL1 axis, a promising therapeutic target in aggressive breast cancers. Oncoimmunology 2016; 5: e1085148.
6.
Gunturi A, McDermott DF. Potential of new therapies like anti-PD1 in kidney cancer. Curr Treat Options Oncol 2014; 15: 137-146.
7.
Sasse S, Reddemann K, Diepstra A, et al. Programmed cell death protein1 (PD1)-expression in the microenvironment of classical Hodgkin lymphoma at relapse after conventional chemotherapy and at relapse on anti-PD1 treatment. Haematologica 2019; 104: e45-e46.
8.
Sasaki A, Nakamura Y, Mishima S, et al. Predictive factors for hyperprogressive disease during nivolumab as anti-PD1 treatment in patients with advanced gastric cancer. Gastric Cancer 2019; 22: 793-802.
9.
Indini A, Di Guardo L, Cimminiello C, et al. Immune-related adverse events correlate with improved survival in patients undergoing anti-PD1 immunotherapy for metastatic melanoma. J Cancer Res Clin Oncol 2019; 145: 511-521.
10.
Wagner MJ, Ricciotti RW, Mantilla J, et al. Response to PD1 inhibition in conventional chondrosarcoma. J Immunother Cancer 2018; 6: 94.
11.
Stenehjem DD, Tran D, Nkrumah MA, et al. PD1/PDL1 inhibitors for the treatment of advanced urothelial bladder cancer. Onco Targets Ther 2018; 11: 5973-5989.
12.
Ho WJ, Yarchoan M, Hopkins A, et al. Association between pretreatment lymphocyte count and response to PD1 inhibitors in head and neck squamous cell carcinomas. J Immunother Cancer 2018; 6: 84.
13.
Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity 2016; 44: 989-1004.
14.
Okamura T, Yamamoto K, Fujio K. Early Growth Response Gene 2-Expressing CD4(+)LAG3(+) Regulatory T Cells: The Therapeutic Potential for Treating Autoimmune Diseases. Front Immunol 2018; 9: 340.
15.
Liu Y, Sorce S, Nuvolone M, et al. Lymphocyte activation gene 3 (Lag3) expression is increased in prion infections but does not modify disease progression. Sci Rep 2018; 8: 14600.
16.
Lee SJ, Jun SY, Lee IH, et al. CD274, LAG3, and IDO1 expressions in tumor-infiltrating immune cells as prognostic biomarker for patients with MSI-high colon cancer. J Cancer Res Clin Oncol 2018; 144: 1005-1014.
17.
Bhagwat B, Cherwinski H, Sathe M, et al. Establishment of engineered cell-based assays mediating LAG3 and PD1 immune suppression enables potency measurement of blocking antibodies and assessment of signal transduction. J Immunol Methods 2018; 456: 7-14.
18.
Zhang Q, Chikina M, Szymczak-Workman AL, et al. LAG3 limits regulatory T cell proliferation and function in autoimmune diabetes. Sci Immunol 2017; 2: eaah4569.
19.
Nakachi S, Sumitomo S, Tsuchida Y, et al. Interleukin-10-producing LAG3(+) regulatory T cells are associated with disease activity and abatacept treatment in rheumatoid arthritis.
20.
Arthritis Res Ther 2017; 19: 97.
21.
Roy S, Coulon PG, Srivastava R, et al. Blockade of LAG-3 Immune Checkpoint Combined With Therapeutic Vaccination Restore the Function of Tissue-Resident Anti-viral CD8(+) T Cells and Protect Against Recurrent Ocular Herpes Simplex Infection and Disease. Front Immunol 2018; 9: 2922.
22.
Ma Q, Liu J, Wu G, et al. Co-expression of LAG3 and TIM3 identifies a potent Treg population that suppresses macrophage functions in colorectal cancer patients. Clin Exp Pharmacol Physiol 2018; 45: 1002-1009.
23.
Li N, Jilisihan B, Wang W, et al. Soluble LAG3 acts as a potential prognostic marker of gastric cancer and its positive correlation with CD8+T cell frequency and secretion of IL-12 and INF-gamma in peripheral blood. Cancer Biomark 2018; 23: 341-351.
24.
Sidaway P. Breast cancer: LAG3 expression indicates favourable outcomes. Nat Rev Clin Oncol 2017; 14: 712.
25.
Ma QY, Huang DY, Zhang HJ, et al. Function and regulation of LAG3 on CD4(+)CD25(-) T cells in non-small cell lung cancer. Exp Cell Res. 2017; 360: 358-364.
26.
Huang RY, Eppolito C, Lele S, et al. LAG3 and PD1 co-inhibitory molecules collaborate to limit CD8+ T cell signaling and dampen antitumor immunity in a murine ovarian cancer model. Oncotarget 2015; 6: 27359-27377.
27.
Zhou G, Noordam L, Sprengers D, et al. Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer. Oncoimmunology 2018; 7: e1448332.
28.
Sasidharan Nair V, Toor SM, Taha RZ, et al. DNA methylation and repressive histones in the promoters of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, PD-L1, and galectin-9 genes in human colorectal cancer. Clin Epigenetics 2018; 10: 104.
29.
Montana M, Garcia ME, Ausias N, et al. Efficacy and safety of nivolumab in patients with non-small cell lung cancer: a retrospective study in clinical practice. J Chemother 2018; 2018: 1-5.
30.
Fujimoto D, Yoshioka H, Kataoka Y, et al. Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: A multicenter retrospective cohort study. Lung Cancer 2018; 119: 14-20.
31.
Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017; 357: 409-413.
32.
Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015; 372: 2509-2520.