Expression of Galectin-9-related immune checkpoint receptors in B-cell acute lymphoblastic leukemia

Document Type : Original Article

Authors

1 Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

2 Molecular and Cell-Biology Research Center, Mazandaran University of Medical Sciences, Sari, Iran

3 Department of Biostatistics and Epidemiology, Mazandaran University of Medical Sciences, Sari, Iran

4 Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran

5 Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

6 Department of Hematology and Oncology, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Sari, Iran

7 Thalassemia Research Center (TRC), Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran

Abstract

Objective(s): Exhausted CD8+ T-cells over-express immune checkpoint receptors (ICRs), which interact with their ligands on malignant cells. However, some ICRs have been reported to be expressed on both T-cells and tumor cells, including V-domain immunoglobulin suppressor of T cell activation (VISTA), Galectin-9, and T-cell immunoglobulin mucin-3 (TIM-3). We aimed to evaluate the mRNA expression of VISTA, Galectin-9, and TIM-3 on CD8+ T-cells and leukemic cells in B-cell acute lymphoblastic leukemia (B-ALL).
Materials and Methods: Samples were obtained from 26 untreated B-ALL patients and 25 control subjects. CD8+ T-cells were isolated using Magnetic Activated Cell Sorting (MACS). Relative gene expression was then evaluated by qRT-PCR with specific primers for VISTA, Galectin-9, and TIM-3. Also, the mRNA expression profile and clinical data of 154 B-ALL patients were obtained from the TARGET.
Results: mRNA expression of Galectin-9 on CD8+ T-cells in B-ALL patients was significantly lower than those in the control group (P=0.043), while VISTA expression was not significantly different between the two study groups (P=0.259). Besides, TIM-3 expression was significantly higher in B-ALL patients than in the control group (P<0.001). Also, data obtained from TARGET showed that the relapse incidence was not significantly different between patients with high and low expression of Galectin-9 and TIM-3 in leukemic cells (P=0.360 and P=0.655, respectively).
Conclusion: Collectively, gene expression results suggest an important role for TIM-3, but not VISTA and Galectin-9, in B-ALL and it seems that TIM-3 could be a candidate for immune checkpoint therapy.

Keywords

Main Subjects

References

1. Loghavi S, Kutok JL, Jorgensen JL. B-acute lymphoblastic leukemia/lymphoblastic lymphoma. Am J Clin Pathol 2015; 144:393-410.
2. García-Escobar I, Sepúlveda J, Castellano D, Cortés-Funes H. Therapeutic management of chronic lymphocytic leukaemia: State of the art and future perspectives. Crit Rev Oncol Hematol 2011; 80:100-113.
3. Wherry EJ. T cell exhaustion. Nat Immunol 2011; 12:492-499.
4. 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.
5. Shi N, Luo Y, Xu Y, Liang J, Ma A, Gan Y, et al. DAP10 predicted the outcome of pediatric b-cell acute lymphoblastic leukemia and was associated with the T-Cell exhaustion. J Oncol 2021; 2021:4824868.
6. Yang RY, Rabinovich GA, Liu FT. Galectins: Structure, function and therapeutic potential. Expert Rev Mol Med 2008; 10:e17.
7. Yasinska IM, Sakhnevych SS, Pavlova L, Teo Hansen Selnø A, Teuscher Abeleira AM, Benlaouer O, et al. The TIM-3-Galectin-9 pathway and its regulatory mechanisms in human breast cancer. Front Immunol 2019; 10:1-13.
8. Gonçalves Silva I, Rüegg L, Gibbs BF, Bardelli M, Fruehwirth A, Varani L, et al. The immune receptor TIM-3 acts as a trafficker in a TIM-3/Galectin-9 autocrine loop in human myeloid leukemia cells. Oncoimmunology 2016; 5:e1195535.
9. Yang R, Sun L, Li CF, Wang YH, Yao J, Li H, et al. Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy. Nat Commun 2021; 12:1-17.
10. Shahbaz S, Dunsmore G, Koleva P, Xu L, Houston S, Elahi S. Galectin-9 and VISTA expression define terminally exhausted T cells in HIV-1 infection. J Immunol 2020; 204:2474-2491.
11. Yasinska IM, Meyer NH, Schlichtner S, Hussain R, Siligardi G, Casely-Hayford M, et al. Ligand-receptor interactions of Galectin-9 and VISTA suppress human T lymphocyte cytotoxic activity. Front Immunol 2020; 11:580557.
12. Shariati S, Ghods A, Zohouri M, Rasolmali R, Talei AR, Mehdipour F, et al. Significance of TIM-3 expression by CD4(+) and CD8(+) T lymphocytes in tumor-draining lymph nodes from patients with breast cancer. Mol Immunol 2020; 128:47-54.
13. Liu J, Yuan Y, Chen W, Putra J, Suriawinata AA, Schenk AD, et al. Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses. Proc Natl Acad Sci U S A 2015; 112:6682-6687.
14. Huang S, Zhao Y, Liao P, Wang J, Li Z, Tan J, et al. Different expression patterns of VISTA concurrent with PD-1, TIM-3, and TIGIT on T cell subsets in peripheral blood and bone marrow from patients with multiple myeloma. Front Oncol 2022; 12:1014904.
15. Huang YH, Zhu C, Kondo Y, Anderson AC, Gandhi A, Russell A, et al. CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature 2015; 517:386-390.
16. Liu S, Xu C, Yang F, Zong L, Qin Y, Gao Y, et al. Natural killer cells induce CD8(+) T cell dysfunction via Galectin-9/TIM-3 in chronic hepatitis B virus infection. Front Immunol 2022; 13:884290.
17. Chauvin JM, Pagliano O, Fourcade J, Sun Z, Wang H, Sander C, et al. TIGIT and PD-1 impair tumor antigen-specific CD8⁺ T cells in melanoma patients. J Clin Invest 2015; 125:2046-2058.
18. Gros A, Robbins PF, Yao X, Li YF, Turcotte S, Tran E, et al. PD-1 identifies the patient-specific CD8⁺ tumor-reactive repertoire infiltrating human tumors. J Clin Invest 2014; 124:2246-2259.
19. Toor SM, Murshed K, Al-Dhaheri M, Khawar M, Abu Nada M, Elkord E. Immune checkpoints in circulating and tumor-infiltrating CD4(+) T cell subsets in colorectal cancer patients. Front Immunol 2019; 10:2936.
20. Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016; 127:2375-2390.
21. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 2001; 25:402-408.
22. Zhou Q, Munger ME, Veenstra RG, Weigel BJ, Hirashima M, Munn DH, et al. Coexpression of TIM-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood 2011; 117:4501-4510.
23. Gardner A, de Mingo Pulido Á, Hänggi K, Bazargan S, Onimus A, Kasprzak A, et al. TIM-3 blockade enhances IL-12-dependent antitumor immunity by promoting CD8(+) T cell and XCR1(+) dendritic cell spatial co-localization. J Immunother Cancer 2022; 10: e003571.
24. Liu JF, Ma SR, Mao L, Bu LL, Yu GT, Li YC, et al. T-cell immunoglobulin mucin 3 blockade drives an antitumor immune response in head and neck cancer. Mol Oncol 2017; 11:235-247.
25. Taghiloo S, Allahmoradi E, Ebadi R, Tehrani M, Hosseini-Khah Z, Janbabaei G, et al. Upregulation of Galectin-9 and PD-L1 immune checkpoints molecules in patients with chronic lymphocytic leukemia. Asian Pac J Cancer Prev 2017; 18:2269-2274.
26. Balajam NZ, Shabani M, Aghaei M, Haghighi M, Kompani F. Study of T-cell immunoglobulin and mucin domain-3 expression profile in peripheral blood and bone marrow of human acute lymphoblastic leukemia patients. J Res Med Sci 2020; 25:1-5.
27. Huang X, Zhang X, Li E, Zhang G, Wang X, Tang T, et al. VISTA: An immune regulatory protein checking tumor and immune cells in cancer immunotherapy. J Hematol Oncol 2020; 13:1-13.
28. Liang T, Wang X, Wang F, Feng E, You G. Galectin-9: A predictive biomarker negatively regulating immune response in glioma patients. World Neurosurg 2019; 132:e455-e462.
29. Kong F, Jin M, Cao D, Jia Z, Liu Y, Jiang J. Galectin-3 not Galectin-9 as a candidate prognosis marker for hepatocellular carcinoma. PeerJ 2020; 8:e9949.
30. Wu Z, Ou J, Liu N, Wang Z, Chen J, Cai Z, et al. Upregulation of TIM-3 is associated with poor prognosis in acute myeloid leukemia. Cancer Med 2023; 12:8956-8969.
31. Zhou E, Huang Q, Wang J, Fang C, Yang L, Zhu M, et al. Up-regulation of TIM-3 is associated with poor prognosis of patients with colon cancer. Int J Clin Exp Pathol 2015; 8:8018-8027.
32. Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 2015; 14:847-856.
Iranian Journal of Basic Medical Sciences
Volume 26, Issue 12
December 2023
Pages 1468-1474

Files

Share

How to cite

Statistics