摘要
背景 转移性肾细胞癌（mRCC）的治疗已从酪氨酸激酶抑制剂（TKI）疗法转向基于免疫检查点抑制剂（ICI）的疗法，治疗效果有所改善，但个体反应不一。本研究结合单细胞RNA测序，比较了PD-1抑制剂+CTLA-4抑制剂和PD-1抑制剂+TKI两种疗法的疗效，研究了接受一线ICI疗法的mRCC患者治疗前低骨骼肌质量（LSMM）和肌骨质疏松对预后的影响。 方法 对2019年11月至2023年3月期间接受基于ICI疗法治疗的90例mRCC患者进行回顾性分析。根据患者是否接受PD-1抑制剂+CTLA-4抑制剂或PD-1抑制剂+TKI联合治疗进行分组。LSMM定义为男性骨骼肌指数低于40.8 cm2/m2，女性骨骼肌指数低于34.9 cm2/m2。肌骨质疏松症的定义是骨骼肌密度，截断值为：BMI < 25 kg/m2 为 41 HU，BMI ≥ 25 kg/m2 为 33 HU。采用卡普兰-梅耶曲线和多变量模型比较了无进展生存期（PFS）和总生存期（OS）。对治疗前样本进行了单细胞 RNA 测序，以比较肌骨软化症患者和非肌骨软化症患者的免疫微环境。 结果 研究队列（女性占 26.7%；中位年龄：60.5 岁）包括 59 名接受 PD-1 抑制剂 + CTLA-4 抑制剂治疗的患者（65.6%）和 31 名接受 PD-1 抑制剂 + TKI 治疗的患者（34.4%）。18.9%的患者存在LSMM，41.1%的患者存在骨质疏松症，各组比例相当。随访期间，29名患者（32.2%）死亡：PD-1抑制剂+CTLA-4抑制剂组16人，PD-1抑制剂+TKI组13人。1年总死亡率为22.2%，PFS率为53.3%。在PD-1抑制剂+TKI组中，肌骨病预示着较差的OS（HR，5.389；p = 0.008）和PFS（HR，2.930；p = 0.022），但在PD-1抑制剂+CTLA-4抑制剂组中，肌骨病对PFS有保护作用（HR，0.461；p = 0.049）。LSMM对两组的结果均无明显影响。单细胞RNA测序显示，肌骨发育不全患者的调节性T细胞中CTLA-4表达较高，效应记忆CD8+T细胞较多，而无肌骨发育不全患者的抗肿瘤非典型单核细胞较多。 结论 在接受PD-1抑制剂+TKI治疗的mRCC患者中，骨质疏松对OS和PFS有负面影响，但在接受PD-1抑制剂+CTLA-4抑制剂治疗的患者中，骨质疏松对PFS有保护作用。与肌营养不良相关的检查点表达和免疫细胞组成的改变可能是导致这些不同反应的原因。
Background
Treatment for metastatic renal cell carcinoma (mRCC) has shifted from tyrosine kinase inhibitor (TKI) therapy to immune checkpoint inhibitor (ICI)–based therapy, improving outcomes but with variable individual responses. This study investigated the prognostic implications of pretreatment low skeletal muscle mass (LSMM) and myosteatosis in patients with mRCC undergoing first-line ICI-based therapies, comparing outcomes between PD-1 inhibitor + CTLA-4 inhibitor and PD-1 inhibitor + TKI, incorporating single-cell RNA sequencing.
Methods
A retrospective analysis was performed on 90 patients with mRCC treated with ICI-based therapies between November 2019 and March 2023. Patients were grouped based on whether they received PD-1 inhibitor + CTLA-4 inhibitor or PD-1 inhibitor + TKI combinations. LSMM was defined as skeletal muscle index below 40.8 cm2/m2 for men and 34.9 cm2/m2 for women. Myosteatosis was defined using skeletal muscle density, with cut-off values < 41 HU for BMI < 25 kg/m2 and < 33 HU for BMI ≥ 25 kg/m2. Progression-free survival (PFS) and overall survival (OS) were compared using Kaplan–Meier curves and multivariable models. Single-cell RNA sequencing was performed on pretreatment samples to compare the immune microenvironment between patients with and without myosteatosis.
Results
The study cohort (26.7% female; median age: 60.5 years) included 59 patients (65.6%) treated with PD-1 inhibitor + CTLA-4 inhibitor and 31 patients (34.4%) treated with PD-1 inhibitor + TKI. LSMM was present in 18.9% of patients, and myosteatosis in 41.1%, with comparable proportions across groups. During follow-up, 29 patients (32.2%) died: 16 in the PD-1 inhibitor + CTLA-4 inhibitor group and 13 in the PD-1 inhibitor + TKI group. The overall 1-year mortality rate was 22.2%, and PFS rate was 53.3%. Myosteatosis predicted poor OS (HR, 5.389; p = 0.008) and PFS (HR, 2.930; p = 0.022) in the PD-1 inhibitor + TKI group but was protective for PFS (HR, 0.461; p = 0.049) in the PD-1 inhibitor + CTLA-4 inhibitor group. LSMM did not significantly affect outcomes in either group. Single-cell RNA sequencing revealed higher CTLA-4 expression in regulatory T cells and more effector memory CD8+ T cells in patients with myosteatosis, whereas patients without myosteatosis had more anti-tumoural non-classical monocytes.
Conclusions
Myosteatosis negatively impacts OS and PFS in patients with mRCC treated with PD-1 inhibitor + TKI therapy but is protective for PFS in those treated with PD-1 inhibitor + CTLA-4 inhibitor therapy. Altered checkpoint expression and immune cell composition associated with myosteatosis may contribute to these differential responses.
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