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肾细胞癌对免疫检查点抑制异常反应的免疫基因组决定因素

原文发布日期：2025-01-09

英文摘要：

摘要翻译：

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肾细胞癌对免疫检查点抑制异常反应的免疫基因组决定因素

Immunogenomic determinants of exceptional response to immune checkpoint inhibition in renal cell carcinoma

原文发布日期：2025-01-09

英文摘要：

Immune checkpoint inhibitors can lead to ‘exceptional’, durable responses in a subset of persons. However, the molecular basis of exceptional response (ER) to immunotherapy in metastatic clear cell renal cell carcinoma (mccRCC) has not been well characterized. Here we analyzed pretherapy genomic and transcriptomic data in treatment-naive persons with mccRCC treated with standard-of-care immunotherapies: (1) combination of programmed cell death protein and ligand 1 (PD1/PDL1) and cytotoxic T lymphocyte-associated protein 4 inhibitors (IO/IO) or (2) combination of PD1/PDL1 and vascular endothelial growth factor (VEGF) receptor inhibitors (IO/VEGF). In the IO/IO cohort, clonal neoantigen load was significantly higher in persons with ER. In the IO/VEGF cohort, ER participants displayed strong enrichment of B cell receptor signaling-related pathways, tertiary lymphoid structure (TLS) signatures and evidence of increased metabolic activity. Our results suggest that ER may be related to clonal neoantigen-driven cytotoxic T cell responses and TLS formation in tumor microenvironments. Therapeutic combinations that elicit both T cell-directed and B cell-directed antitumor immunity may be important to achieve exceptional benefit to IO-based treatment in ccRCC.

摘要翻译：

免疫检查点抑制剂可以在某些患者的特定群体中引发“例外”且持久的反应。然而，在转移性 clear cell renal cell carcinoma（mccRCC）中接受免疫治疗的患者中，异常反应（ER）的分子机制尚未得到充分阐明。我们对接受标准治疗方案免疫治疗的治疗-naïve mccRCC患者的前体基因组和转录组数据进行了分析：（1）联合-programmed cell death protein 和 ligand 1 (PD1/PDL1) 抑制剂和 cytotoxic T lymphocyte-associated protein 4 抑制剂 (IO/IO)，或（2）联合 PD1/PDL1 和 vascular endothelial growth factor (VEGF) 受体抑制剂 (IO/VEGF)。在 IO/IO 对象中，克隆性 neoantigen 载荷量显著高于 ER 的患者。在 IO/VEGF 对象中，ER 参与者表现出 B 细胞受体信号通路的强烈富集、三元淋巴结构 (TLS) 标记物和代谢活动增加的证据。我们的结果表明，ER 可能与克隆性 neoantigen 驱动的 cytotoxic T cell 响应以及肿瘤微环境中的 TLS 形成有关。治疗组合若能同时诱导 T 细胞和 B 细胞介导的抗肿瘤免疫反应，则可能对基于 IO 的治疗在 chronic kidney disease 中实现例外收益具有重要意义。