HDAC Inhibition Unlocks Tumor Plasticity and Enhances Immunotherapy Response in Myc-Driven Small Cell Lung Cancer

Area of Science:

• Oncology
• Immunology
• Epigenetics

Background:

• Small Cell Lung Cancer (SCLC) is an aggressive malignancy with low immunogenicity, potentially evading immune detection via epigenetic mechanisms.
• Histone deacetylase inhibitors (HDACi) are being investigated for their potential to modulate the tumor immune microenvironment.

Purpose of the Study:

• To investigate the effects of entinostat, a class I HDACi, on immune gene expression in SCLC.
• To evaluate the therapeutic potential of combining entinostat with anti-PD-1 immunotherapy in SCLC models.

Main Methods:

• Treatment of human SCLC cells and a Rb1/Trp53/MycT58A (RPM) SCLC mouse model with entinostat.
• Assessment of immune-related gene expression, neuroendocrine phenotype, T-cell infiltration, and tumor growth.
• Combination therapy studies with entinostat and anti-PD-1 immunotherapy in RPM allograft models.

Main Results:

• Entinostat upregulated immune-related genes, immune checkpoint ligands, and antigen presentation machinery in SCLC cells and tumors.
• Entinostat treatment shifted SCLC tumors from a neuroendocrine-high to a neuroendocrine-low phenotype, increasing T-cell infiltration.
• Combination of entinostat with anti-PD-1 immunotherapy suppressed tumor growth and significantly prolonged survival in preclinical SCLC models.

Conclusions:

• Entinostat can reprogram the neuroendocrine status of SCLC, making it more susceptible to immunotherapy.
• Combining entinostat with immune checkpoint blockade, such as anti-PD-1, holds significant therapeutic potential for SCLC.
• These findings support further investigation of entinostat as a neoadjuvant or combination therapy for SCLC to improve patient outcomes.