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Anti-CTLA-4 treatment suppresses hepatocellular carcinoma growth through Th1-mediated cell cycle arrest and apoptosis.

ABSTRACT: Inhibiting the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4)-mediated immune checkpoint system using an anti-CTLA-4 antibody (Ab) can suppress the growth of various cancers, but the detailed mechanisms are unclear. In this study, we established a monoclonal hepatocellular carcinoma cell line (Hepa1-6 #12) and analyzed the mechanisms associated with anti-CTLA-4 Ab treatment. Depletion of CD4+ T cells, but not CD8+ T cells, prevented anti-CTLA-4 Ab-mediated anti-tumor effects, suggesting dependence on CD4+ T cells. Anti-CTLA-4 Ab treatment resulted in recruitment of interferon-gamma (IFN-g)-producing CD4+ T cells, called T-helper 1 (Th1), into tumors, and neutralization of IFN-g abrogated the anti-tumor effects. Moreover, tumor growth suppression did not require major histocompatibility complex (MHC)-I or MHC-II expression on cancer cells. In vitro studies showed that IFN-g can induce cell cycle arrest and apoptosis in tumor cells. Taken together, these data demonstrate that anti-CTLA-4 Ab can exert its anti-tumor effects through Th1-mediated cell cycle arrest and apoptosis.

SUBMITTER: Morihara H

PROVIDER: S-EPMC11302986 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Anti-CTLA-4 treatment suppresses hepatocellular carcinoma growth through Th1-mediated cell cycle arrest and apoptosis.

Morihara Hitomi H Yamada Tomomi T Tona Yumi Y Akasaka Marina M Okuyama Hirohisa H Chatani Natsumi N Shinonome Satomi S Ueyama Azumi A Kuwabara Kenji K Fujio Yasushi Y

PloS one 20240806 8

Inhibiting the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4)-mediated immune checkpoint system using an anti-CTLA-4 antibody (Ab) can suppress the growth of various cancers, but the detailed mechanisms are unclear. In this study, we established a monoclonal hepatocellular carcinoma cell line (Hepa1-6 #12) and analyzed the mechanisms associated with anti-CTLA-4 Ab treatment. Depletion of CD4+ T cells, but not CD8+ T cells, prevented anti-CTLA-4 Ab-mediated anti-tumor effects, suggesting de ...[more]

PMID: 39106430

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Project description:BackgroundHepatocellular carcinoma (HCC) has an increasing incidence and high mortality. Surgical operation is not a comprehensive strategy for liver cancer. Moreover, tolerating systemic chemotherapy is difficult for patients with HCC because hepatic function is often impaired due to underlying cirrhosis. Therefore, a comprehensive strategy for cancer treatment should be developed. DTL (Cdc10-dependent transcript 2) is a critical regulator of cell cycle progression and genomic stability. In our previous study, the upregulation of DTL expression in aggressive HCC correlated positively with tumor grade and poor patient survival. We hypothesize that targeting DTL may provide a novel therapeutic strategy for liver cancer. DTL small interference RNAs were used to knock down DTL protein expression.MethodsA clonogenic assay, immunostaining, double thymidine block, imaging flow cytometry analysis, and a tumor spheroid formation assay were used to analyze the role of DTL in tumor cell growth, cell cycle progression, micronucleation, ploidy, and tumorigenicity.ResultsOur results demonstrated that targeting DTL reduced cell cycle regulators and chromosome segregation genes, resulting in increased cell micronucleation. DTL depletion inhibited liver cancer cell growth, increased senescence, and reduced tumorigenesis. DTL depletion resulted in the disruption of the mitotic proteins cyclin B, CDK1, securin, seprase, Aurora A, and Aurora B as well as the upregulation of the cell cycle arrest gene p21. A rescue assay indicated that DTL should be targeted through TPX2 downregulation for cancer cell growth inhibition. Moreover, DTL silencing inhibited the growth of patient-derived primary cultured HCC cells.ConclusionOur study results indicate that DTL is a potential novel target gene for treating liver cancer through liver cancer cell senescence induction. Furthermore, our results provide insights into molecular mechanisms for targeting DTL in liver cancer cells. The results also indicate several other starting points for future preclinical and clinical studies on liver cancer treatment.

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Anti-CTLA-4 treatment suppresses hepatocellular carcinoma growth through Th1-mediated cell cycle arrest and apoptosis.

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Anti-CTLA-4 treatment suppresses hepatocellular carcinoma growth through Th1-mediated cell cycle arrest and apoptosis.

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