Department of Urology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Clin Cancer Res. 2022 Nov 1;28(21):4807-4819. doi: 10.1158/1078-0432.CCR-22-1279.
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.
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.
琥珀酸脱氢酶缺陷型肾细胞癌（FHRCC）恶性程度高，但目前仍迫切需要有效的治疗方法。本研究旨在分析 FHRCC 的基因组特征和微环境，以及在单细胞水平上导致其对免疫检查点抑制剂（ICI）治疗反应异质性的原因。
对 30 例晚期 FHRCC 患者进行全外显子组测序和免疫组化染色分析。对 4 例接受 ICI 治疗后的患者进行单细胞 RNA 测序。分析了患者的临床特征、治疗效果和随访数据。
中位肿瘤突变负荷仅为 0.14 个突变/兆碱基。免疫组化染色显示肿瘤微环境具有广泛的 CD8+T 细胞浸润，表现为免疫活性。ATM 表达与肿瘤浸润 CD8+T 细胞的百分比呈负相关。轨迹分析表明，尽管持续接受 ICI 治疗，但 CD8+T 细胞的耗竭标志物逐渐上调，凋亡趋势增加。与酪氨酸激酶抑制剂相比，ICI 治疗与提高总缓解率（17.6%比 0%，P = 0.046）和疾病控制率（DCR；64.7%比 12.5%，P = 0.004）相关。在有胚系突变的患者中，ICI 治疗后的缓解率（16.7%比 0%，P = 0.086）和 DCR（66.7%比 14.3%，P = 0.011）较高。
FHRCC 中免疫浸润频繁。ICI 治疗是一种有前途的治疗方案，治疗反应取决于肿瘤浸润淋巴细胞的功能状态。ICI 治疗不能逆转进展性疾病患者 CD8+T 细胞的耗竭，这凸显了需要额外的治疗策略。
