Journal for immunotherapy of cancer · 2026
Epigenetic plus cytokine therapy induces stem-like CD8+ T-cell reservoirs and intratumoral immune niches to overcome anti-PD-1 resistance.
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Minnar Christine Mall, Miyamoto Masaya, Khelifa Asma Sarah, Lui Grace, Lothstein Katherine E, Meler Ainara, Maldonado Maria Del Mar, Hamilton Duane H, Poppe Lisa K, Roller Nicholas, Canubas Kenneth, Zaki George, Lassoued Wiem, Lobanov Alexei, Nousome Darryl, Finney Richard, Cam Margaret, Soon-Shiong Patrick, Gulley James L, Schlom Jeffrey, Gameiro Sofia R
Аннотация
BACKGROUND: Checkpoint blockade (CPB) has limited efficacy in patients with colorectal cancer (CRC), warranting improved therapeutic strategies capable of remodeling the tumor microenvironment. Stem-like TCF1+CD8+ T cells, cytotoxic CD8+ T cells, and lymphoid aggregates have been associated with CPB responsiveness, either individually or as coordinated immune hubs.
METHODS: We evaluated the combination of αPD-1, the class I histone deacetylase inhibitor entinostat, and the IL-15 superagonist N-803 in CPB-resistant murine CRC and breast cancer models with varying antigen presentation deficiencies. Proteomic, transcriptomic, spatial, and functional analyses were completed to identify treatment-specific immune remodeling. Translational relevance was assessed using publicly available CPB-treated cancer genomic datasets and functional assays with patient-derived peripheral blood mononuclear cells (PBMCs).
RESULTS: Triple therapy increased stem-like TCF1+CD8+ T cells in tumor-draining lymph nodes and tumors, concomitant with increased intratumoral cytotoxic GZMB+CD8+ T cells. Therapeutic efficacy was associated with remodeling of the tumor microenvironment, uniquely marked by enrichment of intratumoral immune niches comprising TCF1+ and cytotoxic CD8+ T cells, type 1 conventional dendritic cells, and B cells, along with concerted cytokine and chemokine production. A transcriptional signature derived from triple therapy-induced immune niches predicted favorable clinical responses across multiple CPB-experienced cancer cohorts. These responses were functionally corroborated by increased markers of cytotoxicity in patient-derived PBMCs in vitro.
CONCLUSIONS: Treatment with entinostat, N-803, and αPD-1 boosts anti-tumor intratumoral immune niches comprising TCF1+CD8+ T cells. Collectively, these findings suggest that TCF1+CD8+ T cell immune niches previously associated with αPD-1 responsiveness and lacking in non-responders, including most CRC patients, may be restored by the addition of entinostat and N-803 to αPD-1 therapy to treat αPD-1-refractory patients.
METHODS: We evaluated the combination of αPD-1, the class I histone deacetylase inhibitor entinostat, and the IL-15 superagonist N-803 in CPB-resistant murine CRC and breast cancer models with varying antigen presentation deficiencies. Proteomic, transcriptomic, spatial, and functional analyses were completed to identify treatment-specific immune remodeling. Translational relevance was assessed using publicly available CPB-treated cancer genomic datasets and functional assays with patient-derived peripheral blood mononuclear cells (PBMCs).
RESULTS: Triple therapy increased stem-like TCF1+CD8+ T cells in tumor-draining lymph nodes and tumors, concomitant with increased intratumoral cytotoxic GZMB+CD8+ T cells. Therapeutic efficacy was associated with remodeling of the tumor microenvironment, uniquely marked by enrichment of intratumoral immune niches comprising TCF1+ and cytotoxic CD8+ T cells, type 1 conventional dendritic cells, and B cells, along with concerted cytokine and chemokine production. A transcriptional signature derived from triple therapy-induced immune niches predicted favorable clinical responses across multiple CPB-experienced cancer cohorts. These responses were functionally corroborated by increased markers of cytotoxicity in patient-derived PBMCs in vitro.
CONCLUSIONS: Treatment with entinostat, N-803, and αPD-1 boosts anti-tumor intratumoral immune niches comprising TCF1+CD8+ T cells. Collectively, these findings suggest that TCF1+CD8+ T cell immune niches previously associated with αPD-1 responsiveness and lacking in non-responders, including most CRC patients, may be restored by the addition of entinostat and N-803 to αPD-1 therapy to treat αPD-1-refractory patients.