HDAC Inhibition for Optimized Cellular Immunotherapy of NY-ESO-1-Positive Soft Tissue Sarcoma
Wenjie Gong1,2, Lei Wang1, Maria-Luisa Schubert1
1Department of Internal Medicine V, Heidelberg University Hospital, 69120 Heidelberg, Germany.
Abstract:
Adoptive cell therapy with NY-ESO-1-specific T cells is a promising option for the treatment of soft tissue sarcoma (STS) but achieves only transient tumor control in the majority of cases. A strategy to optimize this cell therapeutic approach might be the modulation of the expression of the cancer-testis antigen NY-ESO-1 using histone deacetylase inhibitors (HDACis). In this study, the ex vivo effect of combining NY-ESO-1-specific T cells with the clinically approved pan HDACis panobinostat or vorionstat was investigated. Our data demonstrated that STS cells were sensitive to HDACis. Administration of HDACi prior to NY-ESO-1-specific T cells exerted enhanced lysis against the NY-ESO-1+ STS cell line SW982. This correlated with an increase in the NY-ESO-1 and HLA-ABC expression of SW982 cells, as well as increased CD25 expression on NY-ESO-1-specific T cells. Furthermore, the immune reactivity of NY-ESO-1-specific CD8+ T cells in terms of cytokine release was enhanced by HDACis. In summary, pretreatment with HDACis represents a potential means of enhancing the cytotoxic efficacy of NY-ESO-1-specific T cells against NY-ESO-1-positive STS.
Insights
Histone deacetylase inhibitors (HDACis) enhance adoptive cell therapy for soft tissue sarcoma (STS). Pre-treating with HDACis boosts NY-ESO-1-specific T cells, improving tumor cell killing and immune response in NY-ESO-1-positive STS.
Area of Science:
- Immunotherapy
- Oncology
- Cancer Research
Background:
- Adoptive cell therapy (ACT) using NY-ESO-1-specific T cells shows promise for soft tissue sarcoma (STS) but offers limited tumor control.
- Modulating NY-ESO-1 expression with histone deacetylase inhibitors (HDACis) is a potential strategy to improve ACT efficacy.
Purpose of the Study:
- To investigate the ex vivo efficacy of combining NY-ESO-1-specific T cells with panobinostat or vorinostat (HDACis) for STS treatment.
- To assess the impact of HDACi pretreatment on STS cell sensitivity, NY-ESO-1 expression, and T cell response.
Main Methods:
- Treatment of NY-ESO-1-positive STS cell line SW982 with panobinostat or vorinostat.
- Co-culture of HDACi-treated STS cells with NY-ESO-1-specific T cells.
- Analysis of STS cell lysis, NY-ESO-1 and HLA-ABC expression, and T cell activation markers (CD25, cytokine release).
Main Results:
- STS cells demonstrated sensitivity to HDACis.
- HDACi pretreatment enhanced the cytotoxic lysis of SW982 cells by NY-ESO-1-specific T cells.
- HDACi treatment increased NY-ESO-1 and HLA-ABC expression on SW982 cells and CD25 expression on T cells.
- HDACis augmented the immune reactivity and cytokine release of NY-ESO-1-specific CD8+ T cells.
Conclusions:
- Pretreatment with HDACis can enhance the cytotoxic efficacy of NY-ESO-1-specific T cells against NY-ESO-1-positive STS.
- Combining HDACis with NY-ESO-1-specific T cell therapy is a promising strategy for improving treatment outcomes in STS.
- This approach warrants further investigation for clinical application in soft tissue sarcoma.
