CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Genomic Characteristics and Single-Cell Profiles After Immunotherapy in Fumarate Hydratase-Deficient Renal Cell Carcinoma.
Genomic Characteristics and Single-Cell Profiles After Immunotherapy in Fumarate Hydratase-Deficient Renal Cell Carcinoma.
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免疫浸润在 FHRCC 中频繁发生。基于 ICI 的治疗是一种有前景的方案，治疗反应取决于 TIL（肿瘤浸润淋巴细胞）的功能状态。基于 ICI 的治疗无法逆转疾病进展患者中 CD8+ T 细胞的耗竭，凸显了需要额外的治疗策略。
延胡索酸水合酶缺陷型肾细胞癌（FHRCC）恶性程度高，但有效治疗的迫切需求仍未得到满足。我们旨在在单细胞水平上分析FHRCC的基因组特征和微环境，以及基于免疫检查点抑制剂（ICI）治疗反应异质性的原因。
对30例晚期FHRCC患者进行了全外显子组测序和IHC染色分析。对4例患者在接受ICI为基础的治疗后进行了单细胞RNA测序。分析了临床特征、治疗效果和随访数据。
中位肿瘤突变负荷仅为每兆碱基0.14个突变。IHC染色显示免疫活跃的肿瘤微环境，其特征为广泛的CD8+ T细胞浸润。ATM表达与肿瘤浸润CD8+ T细胞百分比呈负相关。轨迹分析表明，尽管持续接受基于ICI的治疗，CD8+ T细胞的耗竭标志物逐渐上调，且凋亡趋势增加。与酪氨酸激酶抑制剂相比，基于ICI的治疗与更高的总体缓解率（17.6% vs. 0%，P = 0.046）和疾病控制率（DCR；64.7% vs. 12.5%，P = 0.004）相关。在胚系突变患者中，基于ICI的治疗后ORR（16.7% vs. 0%，P = 0.086）和DCR（66.7% vs. 14.3%，P = 0.011）更高。
Fumarate hydratase-deficient renal cell carcinoma (FHRCC) is highly malignant, but the urgent need for effective treatment remains unmet. We aimed to analyze the genomic characteristics and microenvironment of FHRCC and the cause of heterogeneous response to immune checkpoint inhibitor (ICI)-based treatment at single-cell level. EXPERIMENTAL DESIGN: Whole-exome sequencing and IHC staining analyses were performed in 30 advanced FHRCC patients. Single-cell RNA sequencing following ICI-based treatment was conducted in 4 patients. The clinical characteristics, therapeutic effect, and follow-up data were analyzed.
The median tumor mutation burden was only 0.14 mutations per megabase. IHC staining showed an immune-active tumor microenvironment characterized by extensive CD8+ T-cell infiltration. ATM expression was inversely correlated with percentage of tumor-infiltrating CD8+ T cells. Trajectory analysis indicated gradually upregulated exhausted markers and an increased apoptotic trend of CD8+ T cells despite continuous exposure to ICI-based treatment. ICI-based treatment was associated with improved overall response rate (17.6% vs. 0%, P = 0.046) and disease control rate (DCR; 64.7% vs. 12.5%, P = 0.004) compared with tyrosine kinase inhibitor. Among patients with germline mutation, the ORR (16.7% vs. 0%, P = 0.086) and the DCR (66.7% vs. 14.3%, P = 0.011) were higher after ICI-based treatment.
Immune infiltration is frequent in FHRCC. ICI-based treatment is a promising regimen, and treatment response depends on the functional status of tumor-infiltrating lymphocytes. ICI-based treatment cannot reverse the exhaustion of CD8+ T cells in patients with progressive disease, highlighting the need for additional therapeutic strategies.
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