Epigenetic plus cytokine therapy evades checkpoint blockade resistance by potentiating cytotoxic CD8+ T cells with stem-immunity clusters [ATAC-seq]

Here, we find the combination of anti-PD-1, the class I histone deacetylase inhibitor entinostat, and the IL-15 superagonist N-803 elicited anti-tumor immunity and increased survival in a murine CPB-resistant CRC and in other tumor types with varying antigen presentation deficiencies. Triple therapy increased CRC tumor and draining lymph node stem-like TCF1+CD8+ T cells, and tumor granzyme B+ CD8+ T and NK cells.

Increased stem-immunity clusters comprising TCF1+CD8+ T cells, cDC1, and B cells were observed in tumors with concerted cytokine and chemokine production. Triple therapy also augmented cytotoxicity of patient-derived PBMCs in vitro. Moreover, we identified a biomarker signature of triple therapy‒induced stem-immunity clusters that was associated favorable clinical response across multiple cancers, including CPB-experienced.