Association between cellular immune response and spleen weight in mice with hepatocellular carcinoma

Jiang,Wei; Li,Yu; Zhang,Shuqun; Kong,Guangyao; Li,Zongfang

doi:10.3892/ol.2021.12886

Association between cellular immune response and spleen weight in mice with hepatocellular carcinoma

Authors:
- Wei Jiang
- Yu Li
- Shuqun Zhang
- Guangyao Kong
- Zongfang Li
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Affiliations: Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China, National and Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
Published online on: June 30, 2021 https://doi.org/10.3892/ol.2021.12886
Article Number: 625
Copyright: © Jiang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The spleen is an important site for extramedullary hematopoiesis and tumor immunotolerance. Spleen weight varies with tumor progression and may be a predictor of tumor recurrence. However, to the best of our knowledge, the association between spleen weight and tumor progression remains unclear. The present study revealed a novel role for the spleen in predicting the cellular immune response in tumor‑bearing mice. A murine H22 subcutaneous hepatoma model was established. The spleen weight and tumor weight were measured. The proportion of immune cells in peripheral blood and spleen were detected by flow cytometry. The results demonstrated that the spleen weight of tumor‑bearing mice at day 21 was higher than that of the controls. In addition, spleen weight was identified to be positively correlated with tumor weight. The percentages of CD4⁺ and CD8⁺ T lymphocytes in the spleen were decreased at day 21 after tumor cell inoculation, while those of monocytic‑like myeloid‑derived suppressor cells (M‑MDSCs) and CD11b⁺F4/80⁺ macrophages were increased at day 21 after tumor cell inoculation. Similarly, the percentage of polymorphonuclear‑like MDSCs (PMN‑MDSCs) in the spleen of tumor‑bearing mice was increased at days 7, 14 and 21 after tumor cell inoculation. Notably, spleen weight was negatively correlated with the percentages of CD4⁺ and CD8⁺ T lymphocytes in the spleen, although spleen and tumor weight were positively correlated with the percentages of M‑MDSCs and PMN‑MDSCs in the spleen. Similarly, the percentages of CD8⁺ T lymphocytes in the peripheral blood were decreased, and programmed cell death protein 1 expression on CD8⁺ T lymphocytes was increased at day 21 after tumor cell inoculation. Furthermore, the percentages of M‑MDSCs were increased at day 21 and PMN‑MDSCs in the peripheral blood were increased at days 7, 14 and 21 after tumor cell inoculation. Additionally, spleen and tumor weight were also positively correlated with the percentages of M‑MDSC and PMN‑MDSCs in the peripheral blood of tumor‑bearing mice. Collectively, the findings of the present study suggested that spleen weight may be a predictor of tumor prognosis, since it was directly correlated with tumor weight and the percentages of M‑MDSC and PMN‑MDSCs in tumor‑bearing mice.

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1	Ugel S, Peranzoni E, Desantis G, Chioda M, Walter S, Weinschenk T, Ochando JC, Cabrelle A, Mandruzzato S and Bronte V: Immune tolerance to tumor antigens occurs in a specialized environment of the spleen. Cell Rep. 2:628–639. 2012. View Article : Google Scholar : PubMed/NCBI
2	Marvel D and Gabrilovich DI: Myeloid-derived suppressor cells in the tumor microenvironment: Expect the unexpected. J Clin Invest. 125:3356–3364. 2015. View Article : Google Scholar : PubMed/NCBI
3	Jiang W, Li Y, Wei W, Li JW, Li L, Zhang C, Zhang SQ, Kong GY and Li ZF: Spleen contributes to restraint stress induced hepatocellular carcinoma progression. Int Immunopharmacol. 83:1064202020. View Article : Google Scholar : PubMed/NCBI
4	Xia Y, Wei Y, Li Z-Y, Cai XY, Zhang LL, Dong XR, Zhang S, Zhang RG, Meng R, Zhu F, et al: Catecholamines contribute to the neovascularization of lung cancer via tumor-associated macrophages. Brain Behav Immun. 81:111–121. 2019. View Article : Google Scholar : PubMed/NCBI
5	Wu C, Ning H, Liu M, Lin J, Luo S, Zhu W, Xu J, Wu WC, Liang J, Shao CK, et al: Spleen mediates a distinct hematopoietic progenitor response supporting tumor-promoting myelopoiesis. J Clin Invest. 128:3425–3438. 2018. View Article : Google Scholar : PubMed/NCBI
6	Kumar V, Patel S, Tcyganov E and Gabrilovich DI: The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 37:208–220. 2016. View Article : Google Scholar : PubMed/NCBI
7	Cortez-Retamozo V, Etzrodt M, Newton A, Rauch PJ, Chudnovskiy A, Berger C, Ryan RJ, Iwamoto Y, Marinelli B, Gorbatov R, et al: Origins of tumor-associated macrophages and neutrophils. Proc Natl Acad Sci USA. 109:2491–2496. 2012. View Article : Google Scholar : PubMed/NCBI
8	Cortez-Retamozo V, Etzrodt M, Newton A, Ryan R, Pucci F, Sio SW, Kuswanto W, Rauch PJ, Chudnovskiy A, Iwamoto Y, et al: Angiotensin II drives the production of tumor-promoting macrophages. Immunity. 38:296–308. 2013. View Article : Google Scholar : PubMed/NCBI
9	Han Y, Liu Q, Hou J, Gu Y, Zhang Y, Chen Z, Fan J, Zhou W, Qiu S, Zhang Y, et al: Tumor-Induced Generation of Splenic Erythroblast-like Ter-Cells Promotes Tumor Progression. Cell. 173:634–648.e12. 2018. View Article : Google Scholar : PubMed/NCBI
10	Kristinsson SY, Gridley G, Hoover RN, Check D and Landgren O: Long-term risks after splenectomy among 8,149 cancer-free American veterans: A cohort study with up to 27 years follow-up. Haematologica. 99:392–398. 2014. View Article : Google Scholar : PubMed/NCBI
11	Lv X, Yang F, Guo X, Yang T, Zhou T, Dong X, Long Y, Xiao D and Chen Y: Hypersplenism is correlated with increased risk of hepatocellular carcinoma in patients with post-hepatitis cirrhosis. Tumour Biol. 37:8889–8900. 2016. View Article : Google Scholar : PubMed/NCBI
12	Dubeykovskaya Z, Si Y, Chen X, Worthley DL, Renz BW, Urbanska AM, Hayakawa Y, Xu T, Westphalen CB, Dubeykovskiy A, et al: Neural innervation stimulates splenic TFF2 to arrest myeloid cell expansion and cancer. Nat Commun. 7:105172016. View Article : Google Scholar : PubMed/NCBI
13	Li B, Zhang S, Huang N, Chen H, Wang P, Yang J and Li Z: CCL9/CCR1 induces myeloid derived suppressor cell recruitment to the spleen in a murine H22 orthotopic hepatoma model. Oncol Rep. 41:608–618. 2019.PubMed/NCBI
14	Li B, Zhang S, Huang N, Chen H, Wang P, Li J, Pu Y, Yang J and Li Z: Dynamics of the spleen and its significance in a murine H22 orthotopic hepatoma model. Exp Biol Med (Maywood). 241:863–872. 2016. View Article : Google Scholar : PubMed/NCBI
15	Miller MR, Mandell JB, Beatty KM, Harvey SA, Rizzo MJ, Previte DM, Thorne SH and McKenna KC: Splenectomy promotes indirect elimination of intraocular tumors by CD8⁺ T cells that is associated with IFNγ- and Fas/FasL-dependent activation of intratumoral macrophages. Cancer Immunol Res. 2:1175–1185. 2014. View Article : Google Scholar : PubMed/NCBI
16	Bronte V and Pittet MJ: The spleen in local and systemic regulation of immunity. Immunity. 39:806–818. 2013. View Article : Google Scholar : PubMed/NCBI
17	Wen SW, Everitt SJ, Bedő J, Chabrot M, Ball DL, Solomon B, MacManus M, Hicks RJ, Möller A and Leimgruber A: Spleen volume variation in patients with locally advanced non-small cell lung cancer receiving platinum-based chemo-radiotherapy. PLoS One. 10:e01426082015. View Article : Google Scholar : PubMed/NCBI
18	Jiang W, Li Y, Li ZZ, Sun J, Li JW, Wei W, Li L, Zhang C, Huang C, Yang SY, et al: Chronic restraint stress promotes hepatocellular carcinoma growth by mobilizing splenic myeloid cells through activating β-adrenergic signaling. Brain Behav Immun. 80:825–838. 2019. View Article : Google Scholar : PubMed/NCBI
19	Jiang W, Li Y, Sun J, Li L, Li JW, Zhang C, Huang C, Yang J, Kong GY and Li ZF: Spleen contributes to restraint stress induced changes in blood leukocytes distribution. Sci Rep. 7:65012017. View Article : Google Scholar : PubMed/NCBI
20	Li Y, Jiang W, Li ZZ, Zhang C, Huang C, Yang J, Kong GY and Li ZF: Repetitive restraint stress changes spleen immune cell subsets through glucocorticoid receptor or β-adrenergic receptor in a stage dependent manner. Biochem Biophys Res Commun. 495:1108–1114. 2018. View Article : Google Scholar : PubMed/NCBI
21	Gabrilovich DI: Myeloid-derived suppressor sells. Cancer Immunol Res. 5:3–8. 2017. View Article : Google Scholar : PubMed/NCBI
22	Li L, Duan M, Chen W, Jiang A, Li X, Yang J and Li Z: The spleen in liver cirrhosis: Revisiting an old enemy with novel targets. J Transl Med. 15:1112017. View Article : Google Scholar : PubMed/NCBI
23	McKim DB, Patterson JM, Wohleb ES, Jarrett BL, Reader BF, Godbout JP and Sheridan JF: Sympathetic release of splenic monocytes promotes recurring anxiety following repeated social defeat. Biol Psychiatry. 79:803–813. 2016. View Article : Google Scholar : PubMed/NCBI
24	Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo JL, Kohler RH, Chudnovskiy A, Waterman P, et al: Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science. 325:612–616. 2009. View Article : Google Scholar : PubMed/NCBI
25	Jordan KR, Kapoor P, Spongberg E, Tobin RP, Gao D, Borges VF and McCarter MD: Immunosuppressive myeloid-derived suppressor cells are increased in splenocytes from cancer patients. Cancer Immunol Immunother. 66:503–513. 2017. View Article : Google Scholar : PubMed/NCBI
26	Zhang S, Li ZF, Pan D, Huang C, Zhou R and Liu ZW: Changes of splenic macrophage during the process of liver cancer induced by diethylnitrosamine in rats. Chin Med J (Engl). 122:3043–3047. 2009.PubMed/NCBI
27	Mundy-Bosse BL, Thornton LM, Yang HC, Andersen BL and Carson WE: Psychological stress is associated with altered levels of myeloid-derived suppressor cells in breast cancer patients. Cell Immunol. 270:80–87. 2011. View Article : Google Scholar : PubMed/NCBI
28	Wang H, Zou C, Zhao W, Yu Y, Cui Y, Zhang H, e F, Qiu Z, Zou C and Gao X: Juglone eliminates MDSCs accumulation and enhances antitumor immunity. Int Immunopharmacol. 73:118–127. 2019. View Article : Google Scholar : PubMed/NCBI
29	Zheng R and Chen S and Chen S: Correlation between myeloid-derived suppressor cells and S100A8/A9 in tumor and autoimmune diseases. Int Immunopharmacol. 29:919–925. 2015. View Article : Google Scholar : PubMed/NCBI
30	Mohammadpour H, MacDonald CR, Qiao G, Chen M, Dong B, Hylander BL, McCarthy PL, Abrams SI and Repasky EA: β2 adrenergic receptor-mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells. J Clin Invest. 129:5537–5552. 2019. View Article : Google Scholar : PubMed/NCBI
31	Geng J, Yuan Y, Jiao X, Wang R, Liu N, Chen H, Griffin N and Shan F: Novel modulation on myeloid-derived suppressor cells (MDSCs) by methionine encephalin (MENK). Int Immunopharmacol. 68:193–203. 2019. View Article : Google Scholar : PubMed/NCBI
32	Ostrand-Rosenberg S: Myeloid derived-suppressor cells: Their role in cancer and obesity. Curr Opin Immunol. 51:68–75. 2018. View Article : Google Scholar : PubMed/NCBI
33	Ma M, Huang W and Kong D: IL-17 inhibits the accumulation of myeloid-derived suppressor cells in breast cancer via activating STAT3. Int Immunopharmacol. 59:148–156. 2018. View Article : Google Scholar : PubMed/NCBI
34	Jiang K, Li J, Zhang J, Wang L, Zhang Q, Ge J, Guo Y, Wang B, Huang Y, Yang T, et al: SDF-1/CXCR4 axis facilitates myeloid-derived suppressor cells accumulation in osteosarcoma microenvironment and blunts the response to anti-PD-1 therapy. Int Immunopharmacol. 75:1058182019. View Article : Google Scholar : PubMed/NCBI
35	Song MK, Chung JS, Lim SN, Lee GW, Lee SM, Lee NK, Choi JC and Oh SY: Usefulness of spleen volume measured by computed tomography for predicting clinical outcome in primary myelofibrosis. Int J Hematol. 104:476–484. 2016. View Article : Google Scholar : PubMed/NCBI
36	Nous A, Peeters I, Nieboer K, Vanbinst AM, De Keyser J and De Raedt S: Post-stroke infections associated with spleen volume reduction: A pilot study. PLoS One. 15:e02324972020. View Article : Google Scholar : PubMed/NCBI
37	Yoo J, Kim SW, Lee DH, Bae JS and Cho EJ: Prognostic role of spleen volume measurement using computed tomography in patients with compensated chronic liver disease from hepatitis B viral infection. Eur Radiol. 31:1432–1442. 2020. View Article : Google Scholar : PubMed/NCBI
38	Bae JS, Lee DH, Yoo J, Yi NJ, Lee KW, Suh KS, Kim H and Lee KB: Association between spleen volume and the post-hepatectomy liver failure and overall survival of patients with hepatocellular carcinoma after resection. Eur Radiol. 31:2461–2471. 2021. View Article : Google Scholar : PubMed/NCBI
39	Fernández-Placencia R, Golse N, Cano L, Allard MA, Pittau G, Ciacio O, Cunha AS, Castaing D, Salloum C, Azoulay D, et al: Spleen volumetry and liver transient elastography: Predictors of persistent posthepatectomy decompensation in patients with hepatocellular carcinoma. Surgery. 168:17–24. 2020. View Article : Google Scholar
40	Marasco G, Colecchia A, Colli A, Ravaioli F, Casazza G, Reggiani ML, Cucchetti A, Cescon M and Festi D: Role of liver and spleen stiffness in predicting the recurrence of hepatocellular carcinoma after resection. J Hepatol. 70:440–448. 2019. View Article : Google Scholar : PubMed/NCBI
41	Cao ZX, Chen XP and Wu ZD: Effects of splenectomy in patients with cirrhosis undergoing hepatic resection for hepatocellular carcinoma. World J Gastroenterol. 9:2460–2463. 2003.PubMed/NCBI