前列腺癌中髓质介导免疫疗法耐药性的演变
Aram Lyu1,2,3, Zenghua Fan1, Matthew Clark1
1Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Nature
|December 5, 2024
概括
转移性割抗性前列腺癌患者对免疫检查点抑制剂 (ICI) 有抗性. 通过腺A2A受体 (A2AR) 阻断向SPP1hi-TAM显示出克服这种抗性的希望.
科学领域:
- 免疫学
- 癌症学
- 药理学
背景情况:
- 晚期转移性抵抗割的前列腺癌 (mCRPC) 对免疫检查点抑制剂 (ICI) 呈现耐药性.
- 瘤中的免疫抑制性髓状细胞有助于这种抗性,但它们的异质性使向治疗复杂化.
- 之前针对殖民地刺激因子-1受体 (CSF1R) 的尝试已被证明是临床无效的.
研究的目的:
- 确定在mCRPC中导致免疫疗法耐药性的特定髓状细胞群.
- 阐明这些细胞调解免疫抑制的机制.
- 评估针对这些机制的新疗法,以改善mCRPC治疗.
主要方法:
- 在前列腺癌疾病连续性中对患者活检进行单细胞分析.
- 在体内研究巨细胞功能和ICI耐药性的同基因小鼠模型.
- 药理上抑制了腺A2A受体 (A2ARs) 和编程细胞死亡蛋白1 (PD-1) 的阻断.
- 在mCRPC患者中评估A2AR抑制 (ciforadenant) 与PD- L1阻断 (atezolizumab) 的临床试验.
主要成果:
- 在前列腺癌进展过程中,一个独特的SPP1高瘤相关巨细胞群 (SPP1hi-TAMs) 丰富为mCRPC.
- 在临床前模型中,SPP1hi- TAM抑制CD8+T细胞活性,并促进ICI耐药性.
- 通过A2ARs传递腺素信号,可以调解SPP1hi-TAM诱导的免疫抑制.
- 抑制A2ARs可以逆转免疫抑制,增强T细胞活性,并在体内改善对PD-1阻断的反应.
- 在mCRPC患者中,使用ciforadenant和atezolizumab的临床联合治疗引起了反应.
- 在患者中,A2AR抑制降低了SPP1hi- TAM的丰度,证实了该途径的参与.
结论:
- 通过腺信号传递,SPP1hi-TAM是mCRPC中ICI耐药性的关键媒介.
- 向A2ARs是克服mCRPC免疫疗法耐药性的一个有希望的策略.
- 在mCRPC中,SPP1hi-TAM可作为治疗疗效的预测生物标志物.
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