肿瘤细胞治疗研究
英文原题：Mutant p53 epigenetically rewires CXCL10 to promote CD8⁺ T-cell infiltration and enhance the anti-PD-1 response in advanced prostate cancer.
Mutant p53 epigenetically rewires CXCL10 to promote CD8⁺ T-cell infiltration and enhance the anti-PD-1 response in advanced prostate cancer.
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这些发现表明，突变型 p53 可通过协调的表观遗传、代谢及基质-免疫重塑，将免疫冷前列腺肿瘤重编程为免疫热生态系统。因此，TP53 突变状态可能有助于患者分层以及靶向 CXCL10–CXCR3 轴的联合免疫治疗策略。
TP53突变常与免疫抑制性肿瘤微环境和对免疫检查点阻断（ICB）的耐药性相关。然而，其在晚期前列腺癌中塑造抗肿瘤免疫的机制作用仍不清楚。
我们构建了携带Trp53 p.R245Q敲入突变（与人TP53 p.R248Q同源）的CRISPR-Cas9工程化小鼠前列腺癌模型。在体内评估了肿瘤生长及对抗PD-1治疗的反应。进行了单细胞RNA测序和整合免疫谱分析，以表征基质和免疫重塑。使用染色质免疫沉淀试验评估突变型p53在Cxcl10启动子处的结合及组蛋白修饰。统计学显著性根据需要采用Student's t检验、Wilcoxon秩和检验以及单因素/双因素ANOVA进行评估。
突变型p53加速了肿瘤进展，却在原本具有抑制性的微环境中意外增强了对anti-PD-1治疗的应答。单细胞转录组学揭示了上皮谱系和代谢重编程，伴随癌症相关成纤维细胞的耗竭以及向免疫允许性基质状态的转变。免疫分析显示细胞毒性CD8⁺颗粒酶B⁺ T细胞浸润增加，淋巴和血管特征增强。在机制上，突变型p53占据Cxcl10启动子，通过富集H3K4me3同时减少抑制性组蛋白标记来重塑局部染色质，并转录上调Cxcl10。这建立了一个CXCL10–CXCR3趋化轴，促进细胞毒性CD8⁺ T细胞的募集并使肿瘤对PD-1阻断敏感。一致地，队列分析进一步支持高CXCL10表达与免疫激活及ICB临床获益相关。
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.
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. Single-cell RNA sequencing and integrated immune profiling were performed to characterize stromal and immune remodeling. Chromatin immunoprecipitation assays were used to assess mutant p53 binding and histone modifications at the Cxcl10 promoter. Statistical significance was assessed using Student’s t-test, Wilcoxon rank-sum test, and one-/two-way ANOVA, as appropriate.
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. This established a CXCL10–CXCR3 chemotactic axis that promoted recruitment of cytotoxic CD8⁺ T cells and sensitized tumors to PD-1 blockade. Consistently, cohort analysis further supported that high CXCL10 expression correlated with immune activation and clinical benefit from ICB.
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.
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