PO.BCS01.04 · 生物信息与计算
减瘤性肾切除术联合免疫检查点抑制剂诱导转移性肾细胞癌全身免疫重塑的多模态单细胞分析
Multimodal single-cell analysis of systemic immune remodeling induced by cytoreductive nephrectomy combined with immune checkpoint inhibitors in metastatic renal cell carcinoma
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摘要 Abstract
中文摘要
背景：在免疫肿瘤学时代，减瘤性肾切除术（CN）在转移性肾细胞癌（mRCC）中的作用仍不确定。诸如PROBE（NCT04510597）和NORDICSUN（NCT03977571）等正在进行的试验聚焦于延迟CN与不行CN的对比，但均未纳入前置CN组。为填补这一空白，我们开展了一项多模态单细胞分析，比较前置CN、延迟CN和不行CN联合ICI的免疫学效应。
方法：我们对5例接受不同治疗顺序的CN和ICI治疗的患者的外周血单个核细胞（PBMC）样本进行了整合bulk RNA-seq、scRNA-seq、CITE-seq和TCR-seq的多模态单细胞测序。汇集了跨治疗时间点采集的11份PBMC样本，进行基因分型，并采用基于SNP的分配进行去多重化，随后用Seurat工作流进行标准化和处理。Bulk RNA-seq和基因分型实现了供体识别和转录组分析，同时联合分析单细胞转录组、表面蛋白组和TCR克隆型数据，以表征与CN联合ICI治疗相关的细胞组分、免疫激活状态和克隆动态。
结果：我们分析了133,943个细胞，鉴定出16种免疫细胞类型。免疫组成因减瘤性肾切除术（CN）和ICI治疗的顺序而异。在前置CN组中，CN增加了记忆B细胞、经典单核细胞和NK细胞，这些变化在纳武利尤单抗（nivolumab）联合伊匹木单抗（ipilimumab）治疗期间持续存在。在延迟CN组中，CN同样扩增了NK细胞，但另外还增加了CD8⁺效应记忆T细胞。转录组、ADT和TCR分析揭示了促成全身免疫重塑的不同免疫状态和克隆扩增模式。
结论：本研究揭示，CN联合ICI根据CN是前置还是延迟进行而产生不同的免疫效应。虽然两种方法均增加了NK细胞，但B细胞和T细胞反应在两组间存在差异。我们的多模态单细胞分析进一步鉴定出与每种方法相关的不同转录、蛋白组和克隆变化。尽管CN的最佳时机仍不确定，但这些发现凸显了进一步研究的必要性，以完善患者选择并指导mRCC中CN与ICI治疗的整合。
查看英文原文 English abstract
Background: The role of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) remains uncertain in the immuno-oncology era. Ongoing trials such as PROBE (NCT04510597) and NORDICSUN (NCT03977571), focus on deferred CN versus no CN, but neither includes an upfront CN arm. To address this gap, we performed a multimodal single-cell analysis comparing the immunological effects of upfront CN, deferred CN, and no CN in combination with ICIs.
Methods: We performed multimodal single-cell sequencing integrating bulk RNA-seq, scRNA-seq, CITE-seq, and TCR-seq on peripheral blood mononuclear cell (PBMC) samples obtained from five patients undergoing CN and ICI therapy in different treatment orders. Eleven PBMC samples collected across treatment time points were pooled, genotyped, and demultiplexed using SNP-based assignment, followed by normalization and processing with the Seurat workflow. Bulk RNA-seq and genotyping enabled donor identification and transcriptomic profiling, while single-cell transcriptomic, surface proteomic, and TCR clonotype data were jointly analyzed to characterize cellular components, immune activation states, and clonal dynamics associated with CN in combination with ICI therapy.
Results: We analyzed 133,943 cells and identified 16 immune cell types. Immune composition differed by the sequencing of cytoreductive nephrectomy (CN) and ICI therapy. In the upfront CN group, CN increased memory B cells, classical monocytes, and NK cells, and these changes persisted during nivolumab plus ipilimumab treatment. In the deferred CN group, CN also expanded NK cells but additionally increased CD8⁺ effector memory T cells. Transcriptomic, ADT, and TCR analyses revealed distinct immune states and clonal expansion patterns contributing to systemic immune remodeling.
Conclusions: This study reveals that CN combined with ICIs exerts different immune effects depending on whether CN is performed upfront or deferred. While both approaches increased NK cells, B- and T-cell responses differed between groups. Our multimodal single-cell analysis further identified distinct transcriptional, proteomic, and clonal changes associated with each approach. Although the optimal timing of CN remains uncertain, these findings highlight the need for further investigation to refine patient selection and guide CN integration with ICI therapy in mRCC.
利益披露 Disclosure
S. Park, None..
B. Hwang, None.