HDACi 促进肿瘤微环境的炎症重塑，以增强表位扩展和抗肿瘤免疫

Adoptive cell therapy (ACT) with tumor-specific memory T cells has shown increasing efficacy in regressing solid tumors.

However, tumor antigen heterogeneity represents a longitudinal challenge for durable clinical responses due to the therapeutic selective pressure for immune escape variants.

Here, we demonstrated that delivery of the class I histone deacetylase inhibitor MS-275 promoted sustained tumor regression by synergizing with ACT in a coordinated manner to enhance cellular apoptosis.

We found that MS-275 altered the tumor inflammatory landscape to support antitumor immunoactivation through the recruitment and maturation of cross-presenting CD103+ and CD8+ DCs and depletion of Tregs. Activated endogenous CD8+ T cell responses against nontarget tumor antigens were critically required for the prevention of tumor recurrence.

Importantly, MS-275 altered the immunodominance hierarchy by directing epitope spreading toward the endogenous retroviral tumor-associated antigen p15E.

Our data suggest that MS-275 in combination with ACT multimechanistically enhanced epitope spreading and promoted long-term clearance of solid tumors.