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Mass Cytometry Analysis of Systemic and Local Immune Responses in Hepatocellular Carcinoma
Published on: April 25, 2025
Comparative analysis of various tumor-associated antigen-specific t-cell responses in patients with hepatocellular
Eishiro Mizukoshi1, Yasunari Nakamoto, Kuniaki Arai
1Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
Unlabelled:
Many tumor-associated antigens (TAAs) recognized by cytotoxic T cells (CTLs) have been identified during the last two decades and some of them have been used in clinical trials. However, there are very few in the field of immunotherapy for hepatocellular carcinoma (HCC) because there have not been comparative data regarding CTL responses to various TAAs. In the present study, using 27 peptides derived from 14 different TAAs, we performed comparative analysis of various TAA-specific T-cell responses in 31 HCC patients to select useful antigens for immunotherapy and examined the factors that affect the immune responses to determine a strategy for more effective therapy. Twenty-four of 31 (77.4%) HCC patients showed positive responses to at least one TAA-derived peptide in enzyme-linked immunospot assay. The TAAs consisting of cyclophilin B, squamous cell carcinoma antigen recognized by T cells (SART) 2, SART3, p53, multidrug resistance-associated protein (MRP) 3, alpha-fetoprotein (AFP) and human telomerase reverse transcriptase (hTERT) were frequently recognized by T cells and these TAA-derived peptides were capable of generating peptide-specific CTLs in HCC patients, which suggested that these TAAs are immunogenic. HCC treatments enhanced TAA-specific immune responses with an increased number of memory T cells and induced de novo T-cell responses to lymphocyte-specific protein tyrosine kinase, human epidermal growth factor receptor type 2, p53, and hTERT. Blocking cytotoxic T-lymphocyte antigen-4 (CTLA-4) resulted in unmasking of TAA-specific immune responses by changing cytokine and chemokine profiles of peripheral blood mononuclear cells stimulated by TAA-derived peptides.
Conclusion:
Cyclophilin B, SART2, SART3, p53, MRP3, AFP, and hTERT were immunogenic targets for HCC immunotherapy. TAA-specific immunotherapy combined with HCC treatments and anti-CTLA-4 antibody has the possibility to produce stronger tumor-specific immune responses.
Insights
This study identified key tumor-associated antigens (TAAs) like cyclophilin B and AFP as immunogenic targets for hepatocellular carcinoma (HCC) immunotherapy. Combining HCC treatments with TAA immunotherapy and anti-CTLA-4 antibodies may enhance anti-tumor immune responses.
Area of Science:
- Immunology
- Oncology
- Cancer Immunotherapy
Background:
- Limited comparative data exists for cytotoxic T-cell (CTL) responses to tumor-associated antigens (TAAs) in hepatocellular carcinoma (HCC) immunotherapy.
- Identifying immunogenic TAAs is crucial for developing effective HCC immunotherapies.
Purpose of the Study:
- To conduct a comparative analysis of TAA-specific T-cell responses in HCC patients.
- To identify immunogenic TAAs for HCC immunotherapy.
- To examine factors influencing immune responses for optimizing therapy strategies.
Main Methods:
- Analysis of T-cell responses to 27 peptides derived from 14 TAAs in 31 HCC patients using enzyme-linked immunospot (ELISPOT) assay.
- Evaluation of TAA-specific immune responses following HCC treatments.
- Assessment of immune response modulation by blocking cytotoxic T-lymphocyte antigen-4 (CTLA-4).
Main Results:
- 77.4% of HCC patients responded to at least one TAA-derived peptide.
- Cyclophilin B, SART2, SART3, p53, MRP3, AFP, and hTERT were frequently recognized TAAs, indicating their immunogenicity.
- HCC treatments enhanced TAA-specific immunity, and anti-CTLA-4 therapy unmasked TAA-specific responses.
Conclusions:
- Cyclophilin B, SART2, SART3, p53, MRP3, AFP, and hTERT are promising immunogenic targets for HCC immunotherapy.
- Combination therapy including TAA-specific immunotherapy, HCC treatments, and anti-CTLA-4 antibodies shows potential for enhanced tumor-specific immune responses.
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