Effect of entinostat on NK cell-mediated cytotoxicity against osteosarcoma cells and osteosarcoma lung metastasis
Simin Kiany1, Gangxiong Huang1, Eugenie S Kleinerman1
1Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract:
There is a crucial need for a new therapeutic approach for osteosarcoma (OS) lung metastasis since this disease remains the main cause of mortality in OS. We previously demonstrated that natural killer (NK) cell therapy has minimal efficacy against OS metastasis. This study determined whether the histone deacetylase inhibitor entinostat could immunosensitize OS cells to NK cell lysis and increases the efficacy of NK cell therapy for OS lung metastasis. Entinostat upregulated ligands for NK cell-activating receptors (major histocompatibility complex [MHC] class I polypeptide-related chain A [MICA] and B [MICB]; UL16 binding proteins 1, 2, 5, and 6; and CD155) on OS cells both in vitro and in vivo and led to more susceptibility to NK cell-mediated cytotoxicity in vitro. Importantly, entinostat did not change NK cell viability, receptor expression, or function within the 24-h treatment. We also demonstrated two potential mechanisms by which entinostat enhanced expression of MICA and MICB on OS cells. Although entinostat upregulated ligands for the NK cell activating receptor on OS lung metastasis, it failed to augment the efficacy of NK cell therapy in our nude mouse human OS lung metastasis model. This can be partly explained by our finding that although the infused NK cells were active and functional and could penetrate into the lungs, they failed to infiltrate into the lung nodules. These challenges regarding cellular immunotherapy against solid tumors may be overcome by combination therapy, such as adding a NK cell-activating cytokine (IL-2 or IL-21).
Insights
The histone deacetylase inhibitor entinostat enhanced natural killer (NK) cell recognition of osteosarcoma (OS) cells. However, entinostat did not improve NK cell therapy efficacy against OS lung metastasis in mice.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Osteosarcoma (OS) lung metastasis is a primary cause of mortality.
- Current natural killer (NK) cell therapy shows limited efficacy against OS metastasis.
- Novel therapeutic strategies are needed to enhance NK cell therapy for OS.
Purpose of the Study:
- To investigate if the histone deacetylase inhibitor entinostat can enhance OS cell susceptibility to NK cell lysis.
- To determine if entinostat increases the efficacy of NK cell therapy for OS lung metastasis.
Main Methods:
- Osteosarcoma cells were treated with entinostat in vitro and in vivo.
- NK cell-mediated cytotoxicity was assessed after entinostat treatment.
- Expression of NK cell-activating ligands (MICA, MICB, ULBP, CD155) on OS cells was analyzed.
- The efficacy of combined entinostat and NK cell therapy was evaluated in a mouse model of OS lung metastasis.
Main Results:
- Entinostat upregulated ligands for NK cell-activating receptors on OS cells in vitro and in vivo.
- Entinostat increased OS cell susceptibility to NK cell-mediated cytotoxicity in vitro.
- Entinostat did not affect NK cell viability, receptor expression, or function within 24 hours.
- Entinostat treatment failed to improve the efficacy of NK cell therapy in a mouse model of OS lung metastasis.
- NK cells penetrated lung metastases but did not infiltrate lung nodules.
Conclusions:
- Entinostat can enhance OS cell recognition by NK cells but does not overcome NK cell infiltration barriers in lung metastases.
- Combination therapies, potentially involving NK cell-activating cytokines like IL-2 or IL-21, may be necessary to improve cellular immunotherapy for solid tumors.
