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 explored for their potential to modulate the tumor immune microenvironment.

Purpose of the Study:

• To investigate the effect of entinostat, a class I HDACi, on immune-related gene expression in SCLC.
• To evaluate the efficacy of combining entinostat with anti-PD-1 immunotherapy in preclinical SCLC models.

Main Methods:

• Treatment of human SCLC cells and a Rb1/Trp53/Myc^T58A (RPM) SCLC mouse model with entinostat.
• Analysis of immune-related gene expression, including immune checkpoint ligands and antigen presentation machinery.
• Assessment of tumor phenotype (neuroendocrine status) and combination therapy with anti-PD-1 immunotherapy.

Main Results:

• Entinostat upregulated immune-related genes in human SCLC cells.
• In vivo, entinostat increased immune checkpoint ligands and antigen presentation machinery in RPM tumors, shifting them to a neuroendocrine-low phenotype.
• Combination of entinostat and anti-PD-1 immunotherapy significantly enhanced T-cell infiltration, suppressed tumor growth, and prolonged survival in RPM allograft models.

Conclusions:

• Entinostat can reprogram the immunological landscape and neuroendocrine status of SCLC.
• Combining entinostat with immune checkpoint blockade (anti-PD-1) demonstrates significant therapeutic potential for SCLC by enhancing anti-tumor immunity and improving survival outcomes.