Research on the Regulation of CD4+ Th1 Cell Differentiation and Anti-tumor Function by SOCS1 Factor

Xiaofeng Lu

doi:10.54097/zykkx243

Authors

Xiaofeng Lu

DOI:

https://doi.org/10.54097/zykkx243

Keywords:

SOCS1; Th1 cells; gene editing; tumor Immunology; cell therapy.

Abstract

Suppressor of cytokine signaling 1 (SOCS1) is a key negative regulator of cytokines. It down-regulates key factors such as T-bet by inhibiting the JAK-STAT pathway, NF-κB pathway, etc., thereby suppressing the differentiation of CD4⁺ Th1 cells and forming an immunosuppressive network in the tumor microenvironment. Mature Th1 cells can directly inhibit tumor proliferation, induce tumor cell apoptosis and activate immune cells to exert anti-tumor effects by secreting interferon-γ (IFN-γ). Dendritic cells and bone marrow-derived suppressor cells in the tumor microenvironment increase the expression of SOCS1, reduce the secretion of IL-12, and inhibit the polarization of Th1 cells, thereby facilitating tumor immune escape. In recent years, strategies such as small molecule inhibitors, antibody blockade, and RNA interference have been successively applied in vitro and in animal models, partially restoring the anti-tumor activity mediated by Th1. Meanwhile, the combination of these SOCS1-targeting methods with immune checkpoint inhibitors or chemotherapy also demonstrates the potential for synergistic enhancement. This article systematically reviews the molecular mechanisms by which SOCS1 regulates Th1 differentiation, assesses the research progress and limitations of various intervention strategies, and explores the potential for their combination with existing tumor immunotherapy methods.

Downloads

Download data is not yet available.

References

[1] Stienne C., M. F. Michieletto, M. Benamar, et al. Foxo3 Transcription Factor Drives Pathogenic T Helper 1 Differentiation by Inducing the Expression of Eomes. Immunity, 2016, 45(4): 774-787.

[2] Williams C. G., M. L. Moreira, T. Asatsuma, et al. Plasmodium infection induces phenotypic, clonal, and spatial diversity among differentiating CD4+ T cells. Cell reports, 2024, 43(6): 114317.

[3] Wang S. W., C. Gao, Y. M. Zheng, et al. Current applications and future perspective of CRISPR/Cas9 gene editing in cancer. Molecular cancer, 2022, 21(1): 57.

[4] He M., X. Chen, M. Luo, et al. Suppressor of cytokine signaling 1 inhibits the maturation of dendritic cells involving the nuclear factor kappa B signaling pathway in the glioma microenvironment. Clinical and experimental immunology, 2020, 202(1): 47-59.

[5] Sonar S. A., G. Lal. Differentiation and Transmigration of CD4 T Cells in Neuroinflammation and Autoimmunity. Frontiers in immunology, 2017, 8: 1695.

[6] You Z., M. Timilshina, B. S. Jeong, et al. BJ-2266 ameliorates experimental autoimmune encephalomyelitis through down-regulation of the JAK/STAT signaling pathway. European journal of immunology, 2017, 47(9): 1488-1500.

[7] Kono M., K. Maeda, I. Stocton-Gavanescu, et al. Pyruvate kinase M2 is requisite for Th1 and Th17 differentiation. JCI Insight, 2019, 4(12): e127395.

[8] Pandit M., M. Timilshina, J. H. Chang. LKB1-PTEN axis controls Th1 and Th17 cell differentiation via regulating mTORC1. Journal of molecular medicine, 2021, 99(8): 1139-1150.

[9] Liu Z., L. Wang, P. Gao, et al. Salmonella Pullorum effector SteE regulates Th1/Th2 cytokine expression by triggering the STAT3/SOCS3 pathway that suppresses NF-κB activation. Veterinary microbiology, 2023, 284: 109817.

[10] Gagliani N., S. Huber. Basic Aspects of T Helper Cell Differentiation. Methods in molecular biology, 2017, 15(14): 19-30.

[11] Powell M. D., K. A. Read, B. K. Sreekumar, et al. IL-12 signaling drives the differentiation and function of a TH1-derived TFH1-like cell population. Scientific reports, 2019, 9(1): 13991.

[12] He Z., H. Tian, J. Xing, et al. Full-length transcriptome sequencing of lymphocytes respond to IFN-γ reveals a Th1-skewed immune response in flounder (Paralichthys olivaceus). Fish & shellfish immunology, 2023, 134: 108636.

[13] Jiang Q., X. Huang, W. Yu, et al. mTOR Signaling in the Regulation of CD4+ T Cell Subsets in Periodontal Diseases. Frontiers in immunology, 2022, 13: 827461.

[14] Xhangolli I., B. Dura, G. Lee, et al. Single-cell Analysis of CAR-T Cell Activation Reveals A Mixed TH1/TH2 Response Independent of Differentiation. Genomics Proteomics Bioinformatics, 2019, 17(2): 129-139.

[15] Cecil D., K. H. Park, B. Curtis, et al. Type I T cells sensitize treatment refractory tumors to chemotherapy through inhibition of oncogenic signaling pathways. Journal for immunotherapy of cancer, 2021, 9(3): e002355.

[16] Jairaman A., S. Othy, J. L. Dynes, et al. Piezo1 channels restrain regulatory T cells but are dispensable for effector CD4+ T cell responses. Science advances, 2021, 7(28): eabg5859.

[17] Kruse B., A. C. Buzzai, N. Shridhar, et al. CD4+ T cell-induced inflammatory cell death controls immune-evasive tumours. Nature, 2023, 618(7967): 1033-1040.

[18] Sheikh A. A., J. R. Groom. Transcription tipping points for T follicular helper cell and T-helper 1 cell fate commitment. Cellular & molecular immunology, 2021, 18(3): 528-538.

[19] Mirlekar B., D. Gautam, S. Chattopadhyay. Chromatin Remodeling Protein SMAR1 Is a Critical Regulator of T Helper Cell Differentiation and Inflammatory Diseases. Frontiers in immunology, 2017, 8: 72.

[20] Pfeifhofer-Obermair C., P. Tymoszuk, M. Nairz, et al. Regulation of Th1 T Cell Differentiation by Iron via Upregulation of T Cell Immunoglobulin and Mucin Containing Protein-3 (TIM-3). Frontiers in immunology, 2021, 12: 637809.

[21] Schlabach, M. R., Lin, S., Collester, Z. R., et al. Rational design of a SOCS1-edited tumor-infiltrating lymphocyte therapy using CRISPR/Cas9 screens. The Journal of clinical investigation, 2023,133(24): e163096.

[22] Wu L., X. Liu, J. Lei, et al. Fibrinogen-like protein 2 promotes tumor immune suppression by regulating cholesterol metabolism in myeloid-derived suppressor cells. Journal for immunotherapy of cancer, 2023, 11(12): e008081.