Mutant p53 epigenetically rewires CXCL10 to promote CD8+ T-cell infiltration and enhance the anti-PD-1 response in advanced prostate cancer

Cancer research · Prostate cancer · TP53

Mutant p53 epigenetically activates CXCL10 transcription, which promotes recruitment of cytotoxic CD8+ T cells and sensitizes advanced prostate cancer to anti‑PD‑1 therapy.

Background TP53 mutations are frequently linked to an immunosuppressive tumor microenvironment and resistance to immune checkpoint blockade (ICB). However, their mechanistic role in shaping antitumor immunity in advanced prostate cancer remains unclear. Methods We generated CRISPR‑Cas9‑engineered murine prostate cancer models harboring the Trp53 p.R245Q knock‑in mutation (orthologous to human TP53 p.R248Q). Tumor growth and response to anti‑PD‑1 therapy were evaluated in vivo, and single‑cell RNA sequencing, integrated immune profiling, and chromatin immunoprecipitation assays were performed to characterize stromal, immune remodeling, and mutant p53 binding to the Cxcl10 promoter. Results Mutant p53 accelerated tumor progression yet unexpectedly enhanced responsiveness to anti‑PD‑1 therapy within an otherwise suppressive microenvironment. Single‑cell transcriptomics revealed epithelial lineage and metabolic rewiring, accompanied by depletion of cancer‑associated fibroblasts and a shift toward immune‑permissive stromal states. Immune profiling demonstrated increased infiltration of cytotoxic CD8+ granzyme B+ T cells and augmented lymphoid and vascular features. Mechanistically, mutant p53 occupied the Cxcl10 promoter, remodeled local chromatin by enriching H3K4me3 while reducing repressive histone marks, and transcriptionally upregulated Cxcl10, establishing a CXCL10–CXCR3 chemotactic axis that promoted recruitment of cytotoxic CD8+ T cells and sensitized tumors to PD‑1 blockade. Cohort analysis further supported that high CXCL10 expression correlated with immune activation and clinical benefit from ICB. Conclusions These findings indicate that mutant p53 can reprogram immune‑cold prostate tumors into immune‑hot ecosystems through coordinated epigenetic, metabolic, and stromal‑immune remodeling. TP53 mutation status may therefore inform patient stratification and combinatorial immunotherapeutic strategies targeting the CXCL10–CXCR3 axis.

TP53 mutation status may serve as a biomarker for selecting prostate cancer patients who are more likely to benefit from anti‑PD‑1 therapy and for designing combination therapies that exploit the CXCL10–CXCR3 chemotactic axis.

Evidence level: Állatkísérletes. Állatmodellben vizsgálták.

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