PRDX2 Induces Tumor Immune Evasion by Modulating the HDAC3-Galectin-9 Axis in Lung Adenocarcinoma Cells

Overview

Journal J Transl Med

Publisher Biomed Central

Date 2025 Jan 17

PMID 39825365

Authors

Yunjia Dong

Anqi Cheng

Jiawei Zhou

Jianqiang Guo

Yafeng Liu

Xuan Li

Maoqian Chen

Dong Hu

Jing Wu

Affiliations

Soon will be listed here.

Abstract

Background: PRDX2 is significantly expressed in various cancers and is associated with the proliferation of tumor cells. Nonetheless, the precise mechanism of PRDX2 in tumor immunity remains incompletely understood. This study aims to investigate the impact of PRDX2, which is highly expressed in lung adenocarcinoma, on T cells in the tumor immune microenvironment, and its immune action target to promote the immune escape of lung cancer cells, to provide a theoretical basis for lung adenocarcinoma treatment with PRDX2 as the target.

Methods: Mouse animal models to verify the effect of Conoidin A treatment on tumor growth and T cell infiltration. Flow cytometry and Western blot verified tumor cell apoptosis in the in vitro co-culture system as well as granzyme B and perforin expression in T cells. RNA-Seq was used to obtain the downstream immune molecule. si-RNA knockdown of Galectin-9 was co-cultured with T cells in vitro. Immunofluorescence and Western blot verified that PRDX2 regulates Galectin-9 expression through HDAC3.

Results: PRDX2 expression was negatively correlated with CD8 T cell expression in LUAD patients. Inhibition of PRDX2 significantly enhanced T-cell killing of LUAD cells and reduced tumor load in both in vitro and in vivo models. Mechanistically, Conoidin A or shRNA_PRDX2 decreased Galectin-9 expression by down-regulating the phosphorylation of HDAC3, consequently enhancing the infiltration and function of CD8 T cells.

Conclusions: This study reveals the role of the PRDX2/HDAC3/Galectin-9 axis in LUAD immune escape and indicates Galectin-9 as a promising target for immunotherapy.

Citing Articles

Current advancement of immune function paradox of tumour-infiltrating cells and their immunotherapeutic targets: a mini-review.

Tom V, Jose A, Mallick S, Sasidharan A, Pawar R, Somayaji Y Naunyn Schmiedebergs Arch Pharmacol. 2025; .

PMID: 40063239 DOI: 10.1007/s00210-025-03985-4.

References

Wang S, Chen Z, Zhu S, Lu H, Peng D, Soutto M . PRDX2 protects against oxidative stress induced by H. pylori and promotes resistance to cisplatin in gastric cancer. Redox Biol. 2019; 28:101319. PMC: 6811995. DOI: 10.1016/j.redox.2019.101319. View

Zhang X, Gao F, Li N, Zhang J, Dai L, Yang H . Peroxiredoxins and Immune Infiltrations in Colon Adenocarcinoma: Their Negative Correlations and Clinical Significances, an In Silico Analysis. J Cancer. 2020; 11(11):3124-3143. PMC: 7097948. DOI: 10.7150/jca.38057. View

Thanarajasingam G, Thanarajasingam U, Ansell S . Immune checkpoint blockade in lymphoid malignancies. FEBS J. 2016; 283(12):2233-44. DOI: 10.1111/febs.13668. View

Fang J, Chen F, Liu D, Gu F, Chen Z, Wang Y . Prognostic value of immune checkpoint molecules in breast cancer. Biosci Rep. 2020; 40(7). PMC: 7340863. DOI: 10.1042/BSR20201054. View

Yang R, Rabinovich G, Liu F . Galectins: structure, function and therapeutic potential. Expert Rev Mol Med. 2008; 10:e17. DOI: 10.1017/S1462399408000719. View

Nelson K, Knutson S, Soito L, Klomsiri C, Poole L, Fetrow J . Analysis of the peroxiredoxin family: using active-site structure and sequence information for global classification and residue analysis. Proteins. 2011; 79(3):947-64. PMC: 3065352. DOI: 10.1002/prot.22936. View

Zhang X, Ozawa Y, Lee H, Wen Y, Tan T, Wadzinski B . Histone deacetylase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4. Genes Dev. 2005; 19(7):827-39. PMC: 1074320. DOI: 10.1101/gad.1286005. View

Okoye I, Xu L, Motamedi M, Parashar P, Walker J, Elahi S . Galectin-9 expression defines exhausted T cells and impaired cytotoxic NK cells in patients with virus-associated solid tumors. J Immunother Cancer. 2020; 8(2). PMC: 7735134. DOI: 10.1136/jitc-2020-001849. View

Alam S, Li H, Margariti A, Martin D, Zampetaki A, Habi O . Galectin-9 protein expression in endothelial cells is positively regulated by histone deacetylase 3. J Biol Chem. 2011; 286(51):44211-44217. PMC: 3243525. DOI: 10.1074/jbc.M111.242289. View

10.

Ansell S, Lesokhin A, Borrello I, Halwani A, Scott E, Gutierrez M . PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2014; 372(4):311-9. PMC: 4348009. DOI: 10.1056/NEJMoa1411087. View

11.

Sakuishi K, Jayaraman P, Behar S, Anderson A, Kuchroo V . Emerging Tim-3 functions in antimicrobial and tumor immunity. Trends Immunol. 2011; 32(8):345-9. PMC: 3164311. DOI: 10.1016/j.it.2011.05.003. View

12.

Fujita K, Iwama H, Sakamoto T, Okura R, Kobayashi K, Takano J . Galectin-9 suppresses the growth of hepatocellular carcinoma via apoptosis in vitro and in vivo. Int J Oncol. 2015; 46(6):2419-30. DOI: 10.3892/ijo.2015.2941. View

13.

De Franceschi L, Bertoldi M, De Falco L, Franco S, Ronzoni L, Turrini F . Oxidative stress modulates heme synthesis and induces peroxiredoxin-2 as a novel cytoprotective response in β-thalassemic erythropoiesis. Haematologica. 2011; 96(11):1595-604. PMC: 3208676. DOI: 10.3324/haematol.2011.043612. View

14.

Brahmer J, Tykodi S, Chow L, Hwu W, Topalian S, Hwu P . Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012; 366(26):2455-65. PMC: 3563263. DOI: 10.1056/NEJMoa1200694. View

15.

Zhang S, He J, Tang M, Sun H . Prdx2 Upregulation Promotes the Growth and Survival of Gastric Cancer Cells. Pathol Oncol Res. 2019; 26(3):1869-1877. DOI: 10.1007/s12253-019-00783-1. View

16.

Wang D, Wu X, Sun Y . Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response. Signal Transduct Target Ther. 2022; 7(1):331. PMC: 9485144. DOI: 10.1038/s41392-022-01136-2. View

17.

Chen X, Zhao Y, Luo W, Chen S, Lin F, Zhang X . Celastrol induces ROS-mediated apoptosis via directly targeting peroxiredoxin-2 in gastric cancer cells. Theranostics. 2020; 10(22):10290-10308. PMC: 7481428. DOI: 10.7150/thno.46728. View

18.

Sasidharan Nair V, Toor S, Taha R, Shaath H, Elkord E . 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(1):104. PMC: 6080402. DOI: 10.1186/s13148-018-0539-3. View

19.

Seifert A, Reiche C, Heiduk M, Tannert A, Meinecke A, Baier S . Detection of pancreatic ductal adenocarcinoma with galectin-9 serum levels. Oncogene. 2020; 39(15):3102-3113. PMC: 7142017. DOI: 10.1038/s41388-020-1186-7. View

20.

Agarwal A, Mahfouz R, Sharma R, Sarkar O, Mangrola D, Mathur P . Potential biological role of poly (ADP-ribose) polymerase (PARP) in male gametes. Reprod Biol Endocrinol. 2009; 7:143. PMC: 2800114. DOI: 10.1186/1477-7827-7-143. View