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Optimized dose selective HDAC inhibitor tucidinostat overcomes anti-PD-L1 antibody resistance in experimental solid
Pei Zhang1,2, Yang Du2,3, Hua Bai1
1Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China.
Background:
Although immune checkpoint inhibitors (ICIs) have influenced the treatment paradigm for multiple solid tumors, increasing evidence suggests that primary and adaptive resistance may limit the long-term efficacy of ICIs. New therapeutic strategies with other drug combinations are hence warranted to enhance the antitumor efficacy of ICIs. As a novel tumor suppressor, histone deacetylase (HDAC) inhibitor tucidinostat has been successfully confirmed to act against hematological malignancies. However, the underlying mechanisms of action for tucidinostat and whether it can manipulate the tumor microenvironment (TME) in solid tumors remain unclear.
Methods:
Three murine tumor models (4T1, LLC, and CT26) were developed to define the significant role of different doses of tucidinostat in TME. The immunotherapeutic effect of tucidinostat combined with anti-programmed cell death ligand 1 antibody (aPD-L1) was demonstrated. Furthermore, the effect of tucidinostat on phenotypic characteristics of peripheral blood mononuclear cells (PBMCs) from lung cancer patients was investigated.
Results:
With an optimized dose, tucidinostat could alter TME and promote the migration and infiltration of CD8+ T cells into tumors, partially by increasing the activity of C-C motif chemokine ligand 5 (CCL5) via NF-κB signaling. Moreover, tucidinostat significantly promoted M1 polarization of macrophages and increased the in vivo antitumor efficacy of aPD-L1. Tucidinostat also enhanced the expression of the costimulatory molecules on human monocytes, suggesting a novel and improved antigen-presenting function.
Conclusions:
A combination regimen of tucidinostat and aPD-L1 may work synergistically to reduce tumor burden in patients with cancer by enhancing the immune function and provided a promising treatment strategy to overcome ICI treatment resistance.
Insights
Histone deacetylase (HDAC) inhibitor tucidinostat enhances anti-tumor immunity by promoting CD8+ T cell infiltration and macrophage M1 polarization. Combining tucidinostat with anti-PD-L1 antibody offers a promising strategy to overcome immune checkpoint inhibitor resistance in solid tumors.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but face challenges with primary and adaptive resistance.
- Novel therapeutic combinations are needed to enhance ICI efficacy against solid tumors.
- The role of histone deacetylase (HDAC) inhibitor tucidinostat in solid tumors and its impact on the tumor microenvironment (TME) remain largely unexplored.
Purpose of the Study:
- To investigate the effects of tucidinostat on the TME in murine solid tumor models.
- To evaluate the synergistic immunotherapeutic potential of combining tucidinostat with anti-programmed cell death ligand 1 (aPD-L1) antibody.
- To explore tucidinostat's impact on immune cells from lung cancer patients.
Main Methods:
- Utilized three murine solid tumor models (4T1, LLC, CT26) to assess tucidinostat's dose-dependent effects on the TME.
- Administered tucidinostat in combination with aPD-L1 antibody to evaluate in vivo antitumor efficacy.
- Analyzed phenotypic changes in peripheral blood mononuclear cells (PBMCs) from lung cancer patients.
Main Results:
- Tucidinostat, at an optimized dose, promoted CD8+ T cell migration and infiltration into tumors, partly via enhanced C-C motif chemokine ligand 5 (CCL5) activity through NF-κB signaling.
- Tucidinostat significantly induced M1 macrophage polarization and improved the in vivo antitumor efficacy of aPD-L1.
- Tucidinostat enhanced costimulatory molecule expression on human monocytes, suggesting improved antigen-presenting capabilities.
Conclusions:
- Tucidinostat modulates the TME to enhance anti-tumor immune responses.
- The combination of tucidinostat and aPD-L1 demonstrates synergistic potential in reducing tumor burden.
- This combination strategy shows promise for overcoming resistance to immune checkpoint inhibitors in cancer patients.
