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Unraveling the Causal Links Between Immune Traits and Hepatocellular Carcinoma: Insights From a Bi-Directional Mendelian Randomization Study
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Abstract
Background/Aims: Hepatocellular carcinoma (HCC) is significantly influenced by the immune system, which plays a key role in its development, progression, treatment, and prognosis. While observational studies have revealed correlations between circulating immune traits and HCC, their genetic basis and causal links remain unclear. This study aims to investigate the genetic associations and bidirectional causal relationships between immune traits and HCC risk using Mendelian randomization (MR) approaches.
Materials and Methods: Genome-wide association study summary statistics from the FinnGen cohort (R9, including 453 HCC cases and 287137 controls) were used to perform a bidirectional two-sample MR analysis. The causal effects of immune traits on HCC, as well as reverse causality, were assessed. Sensitivity analyses, including heterogeneity and pleiotropy tests, were used to ensure the robustness and validity of the results.
Results: Thirty-nine immune traits were identified to be significantly associated with HCC risk. Elevated levels of 10 immune traits were positively associated with increased HCC risk, while the abundance of 29 immune traits was inversely correlated with HCC incidence. Furthermore, the reverse MR analysis revealed significant causal effects of HCC on 11 immune traits.
Conclusion: This study provides strong evidence of genetic links between systematic immune cell profiles and HCC, shedding light on the mechanisms underlying its onset and progression. These findings identify potential immune biomarkers for early diagnosis and immune-targeted therapies.
Cite this article as: Li J, Wang G, Xiang X, Wang J. Unraveling the causal links between immune traits and hepatocellular carcinoma: Insights from a bi-directional mendelian randomization study. Turk J Gastroenterol. 2025;36(7):420-430.
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References
1. Li X, Ramadori P, Pfister D, Seehawer M, Zender L, Heikenwalder M.
The immunological and metabolic landscape in primary and metastatic liver cancer. Nat Rev Cancer. 2021;21(9):541-557. [CrossRef]
2.Ringelhan M, Pfister D, O’connor T, Pikarsky E, Heikenwalder M. The
immunology of hepatocellular carcinoma. Nat Immunol. 2018;19(3):
222-232. [CrossRef]
3.Cheng A-L, Hsu C, Chan SL, Choo S-P, Kudo M. Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma. J Hepatol. 2020;72(2):307-319. [CrossRef]
4.Sun R, Li J, Lin X, et al. Peripheral immune characteristics of hepatitis B virus-related hepatocellular carcinoma. Front Immunol.
2023;14:1079495. [CrossRef]5.Hong YM, Yoon KT, Hwang TH, Cho M. Pretreatment peripheral
neutrophils, lymphocytes and monocytes predict long-term survival
in hepatocellular carcinoma. BMC Cancer. 2020;20(1):937.
[CrossRef]
6.He MM, Lo CH, Wang K, et al. Immune-mediated diseases associated with cancer risks. JAMA Oncol. 2022;8(2):209-219. [CrossRef]
7.Zhu M, Ma Z, Zhang X, et al. C-reactive protein and cancer risk: a
pan-cancer study of prospective cohort and Mendelian randomization analysis. BMC Med. 2022;20(1):301. [CrossRef]
8.Yin Q, Yang Q, Shi W, et al. Mendelian randomization analyses of
chronic immune-mediated diseases, circulating inflammatory biomarkers, and cytokines in relation to liver cancer. Cancers (Basel).
2023;15(11):2930. [CrossRef]
9.Qin J, Zhang L, Ke B, Liu T, Kong C, Jin C. Causal relationships
between circulating inflammatory factors and IgA vasculitis: a bidirectional Mendelian randomization study. Front Immunol.
2023;14:1248325. [CrossRef]
10. Orrù V, Steri M, Sidore C, et al. Complex genetic signatures in
immune cells underlie autoimmunity and inform therapy. Nat Genet.
2020;52(10):1036-1045. [CrossRef]
11. 1000 Genomes Project Consortium, Auton A, Brooks LD, et al. A
global reference for human genetic variation. Nature.
2015;526(7571):68-74. [CrossRef]
12. Kamat MA, Blackshaw JA, Young R, et al. PhenoScanner V2: an
expanded tool for searching human genotype-phenotype associations. Bioinformatics. 2019;35(22):4851-4853. [CrossRef]
13. Huang J, Li X, Hong J, et al. Inflammatory bowel disease increases
the risk of hepatobiliary pancreatic cancer: A two-sample Mendelian
randomization analysis of European and East Asian populations.
Cancer Med. 2023;12(12):13599-13609. [CrossRef]
14. Burgess S, Thompson SG. Interpreting findings from Mendelian
randomization using the MR-Egger method. Eur J Epidemiol.
2017;32(5):377-389. [CrossRef]
15. Gitlin AD, Nussenzweig MC. Immunology: fifty years of B lymphocytes. Nature. 2015;517(7533):139-141. [CrossRef]
16. Dong MP, Thuy LTT, Hoang DV, et al. Soluble immune checkpoint
protein CD27 is a novel prognostic biomarker of hepatocellular carcinoma development in hepatitis C virus-sustained virological
response patients. Am J Pathol. 2022;192(10):1379-1396. [CrossRef]
17. Khlaiphuengsin A, Chuaypen N, Sodsai P, et al. Decreased of
BAFF-R expression and B cells maturation in patients with hepatitis
B virus-related hepatocellular carcinoma. World J Gastroenterol.
2020;26(20):2645-2656. [CrossRef]
18. Engblom C, Pfirschke C, Pittet MJ. The role of myeloid cells in
cancer therapies. Nat Rev Cancer. 2016;16(7):447-462. [CrossRef]
19. Pang L, Yeung OWH, Ng KTP, et al. Postoperative plasmacytoid
dendritic cells secrete IFNα to promote recruitment of myeloidderived suppressor cells and drive hepatocellular carcinoma recurrence. Cancer Res. 2022;82(22):4206-4218. [CrossRef]
20.Osman HA, Nafady-Hego H, Nasif KA, et al. Peripheral mononuclear cells surface markers evaluation in different stages of hepatocellular carcinoma; in a trial for early and accurate diagnosis in
patients with post-hepatitis liver cirrhosis and unremarkable raised
AFP. Int J Gen Med. 2023;16:1047-1058. [CrossRef]
21. Pardee AD, Shi J, Butterfield LH. Tumor-derived α-fetoprotein
impairs the differentiation and T cell stimulatory activity of human
dendritic cells. J Immunol. 2014;193(11):5723-5732. [CrossRef]
22.Álvarez-Sánchez N, Cruz-Chamorro I, Díaz-Sánchez M, Lardone PJ, Guerrero JM, Carrillo-Vico A. Peripheral CD39-expressing T
regulatory cells are increased and associated with relapsing-remitting multiple sclerosis in relapsing patients. Sci Rep. 2019;9(1):2302.
[CrossRef]
23.Heymann F, Tacke F. Immunology in the liver--from homeostasis
to disease. Nat Rev Gastroenterol Hepatol. 2016;13(2):88-110.
[CrossRef]
24.Wang J, Ling S, Ni J, Wan Y. Novel γδ T cell-based prognostic
signature to estimate risk and aid therapy in hepatocellular carcinoma. BMC Cancer. 2022;22(1):638. [CrossRef]
25.Harmon C, Zaborowski A, Moore H, et al. γδ T cell dichotomy with
opposing cytotoxic and wound healing functions in human solid
tumors. Nat Cancer. 2023;4(8):1122-1137. [CrossRef]
26.Suimon Y, Kase S, Miura I, Ishijima K, Ishida S. Alteration of cell
surface markers CD38 and CD138 in Lymphoproliferative Disorders
in the Ocular Adnexa. In: Anticancer Res. 2020;40(4):2019-2023.
[CrossRef]
27. Ng HHM, Lee RY, Goh S, et al. Immunohistochemical scoring of
CD38 in the tumor microenvironment predicts responsiveness to
anti-PD-1/PD-L1 immunotherapy in hepatocellular carcinoma. J
Immunother Cancer. 2020;8(2):e000987. [CrossRef]
28.Xiang X, Wang J, Lu D, Xu X. Targeting tumor-associated macrophages to synergize tumor immunotherapy. Signal Transduct Target Ther. 2021;6(1):75. [CrossRef]
29.Xie M, Lin Z, Ji X, et al. FGF19/FGFR4-mediated elevation of ETV4
facilitates hepatocellular carcinoma metastasis by upregulating
PD-L1 and CCL2. J Hepatol. 2023;79(1):109-125. [CrossRef]
30.Gao RQ, Sun JH, Ma YH, et al. Circulating the HLA-DR+ T cell ratio
is a prognostic factor for recurrence of patients with hepatocellular
carcinoma after curative surgery. J Oncol. 2023;2023:1875153.
[CrossRef]