人源化小鼠揭示小细胞肺癌对免疫-放疗联合治疗的 T 细胞浸润表型
SCLC humanized mice identify T cell infiltration phenotypes in response to combination immune-radiation therapies.
作者
作者单位
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
摘要
中文
分子小细胞肺癌（SCLC）亚型（ASCL1、NEUROD1、POU2F3 和 inflamed）具有不同的免疫背景，但临床前模型仍然有限。我们评估了外周血单个核细胞（PBMC）人源化小鼠（hu-mice）作为平台，以捕捉亚型特异性肿瘤-免疫相互作用和对三联方案 AZD1390（ATM 抑制剂）、放疗（RT）和 durvalumab（aPDL1）的治疗敏感性。将所有分子亚型代表的 SCLC 细胞系植入人源化小鼠，虽然 T 细胞浸润在不同亚型间不同，但 SCLC-inflamed 细胞系表现出最高水平的浸润。浸润的 CD8+ T 细胞迅速获得耗竭标志物 PD1、CD39 和 TOX。虽然 aPDL1 单药仅在 inflamed SBC5 细胞系中实现了肿瘤控制，但 AZD1390 联合 RT 上调趋化因子表达（CCL5 和 CXCL10）并增加表面 PDL1，在体内使先前无反应的异种移植物敏感。反应性异种移植物显示 CD39+CD103+ 肿瘤反应性 T 细胞富集，并减少终末耗竭（TCF1-TOX+）。总体而言，PBMC 人源化小鼠可能有效重现 SCLC 免疫背景，并指导联合策略的开发以克服 aPDL1 耐药。
English
Molecular small cell lung cancer (SCLC) subtypes (ASCL1, NEUROD1, POU2F3, and inflamed) display distinct immune contextures, but preclinical modeling remains limited. We evaluated peripheral blood mononuclear cell (PBMC) humanized mice (hu-mice) as a platform to capture subtype-specific tumor-immune interactions and therapeutic sensitivity to the triplet regimen: AZD1390 (ATM inhibitor), radiotherapy (RT), and durvalumab (aPDL1). SCLC cell lines representing all molecular subtypes were engrafted into hu-mice, and while T cell infiltration varied across subtypes, SCLC-inflamed cell lines exhibited the highest levels of infiltration. Infiltrating CD8+ T cells rapidly acquired exhaustion markers PD1, CD39, and TOX. Although aPDL1 monotherapy achieved tumor control only in the inflamed SBC5 cell line, combination AZD1390 and RT upregulated chemokine expression (CCL5 and CXCL10) and increased surface PDL1 to sensitize previously non-responsive xenografts in vivo. Responding xenografts showed enrichment of CD39+CD103+ tumor-reactive T cells with reduced terminal exhaustion (TCF1-TOX+). Overall, PBMC hu-mice may effectively recapitulate SCLC immune contextures and guide development of combinatorial strategies to overcome aPDL1 resistance.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 4.5
- 新锐分区
- 3区