Yuan Shijin, Xia Yan, Dai Guangwei, Rao Shun, Hu Rongrong, Gao Yuzhen, Qiu Qing, Wu Chenghao, Qiao Sai, Xu Yinghua, Xie Xinyou, Lou Haizhou, Wang Xian, Zhang Jun
Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
J Zhejiang Univ Sci B. 2025 Apr 23;26(4):371-392. doi: 10.1631/jzus.B2300679.
Recent data suggest that vascular endothelial growth factor receptor inhibitor (VEGFRi) can enhance the anti-tumor activity of the anti-programmed cell death-1 (anti-PD-1) antibody in colorectal cancer (CRC) with microsatellite stability (MSS). However, the comparison between this combination and standard third-line VEGFRi treatment is not performed, and reliable biomarkers are still lacking. We retrospectively enrolled MSS CRC patients receiving anti-PD-1 antibody plus VEGFRi (combination group, =54) or VEGFRi alone (VEGFRi group, =32), and their efficacy and safety were evaluated. We additionally examined the immune characteristics of the MSS CRC tumor microenvironment (TME) through single-cell and spatial transcriptomic data, and an MSS CRC immune cell-related signature (MCICRS) that can be used to predict the clinical outcomes of MSS CRC patients receiving immunotherapy was developed and validated in our in-house cohort. Compared with VEGFRi alone, the combination of anti-PD-1 antibody and VEGFRi exhibited a prolonged survival benefit (median progression-free survival: 4.4 vs. 2.0 months, =0.0024; median overall survival: 10.2 vs. 5.2 months, =0.0038) and a similar adverse event incidence. Through single-cell and spatial transcriptomic analysis, we determined ten MSS CRC-enriched immune cell types and their spatial distribution, including naive CD4 T, regulatory CD4 T, CD4 Th17, exhausted CD8 T, cytotoxic CD8 T, proliferated CD8 T, natural killer (NK) cells, plasma, and classical and intermediate monocytes. Based on a systemic meta-analysis and ten machine learning algorithms, we obtained MCICRS, an independent risk factor for the prognosis of MSS CRC patients. Further analyses demonstrated that the low-MCICRS group presented a higher immune cell infiltration and immune-related pathway activation, and hence a significant relation with the superior efficacy of pan-cancer immunotherapy. More importantly, the predictive value of MCICRS in MSS CRC patients receiving immunotherapy was also validated with an in-house cohort. Anti-PD-1 antibody combined with VEGFRi presented an improved clinical benefit in MSS CRC with manageable toxicity. MCICRS could serve as a robust and promising tool to predict clinical outcomes for individual MSS CRC patients receiving immunotherapy.
近期数据表明，血管内皮生长因子受体抑制剂（VEGFRi）可增强抗程序性细胞死亡蛋白1（抗PD-1）抗体对微卫星稳定（MSS）的结直肠癌（CRC）的抗肿瘤活性。然而，尚未对该联合疗法与标准三线VEGFRi治疗进行比较，且仍缺乏可靠的生物标志物。我们回顾性纳入了接受抗PD-1抗体加VEGFRi治疗的MSS CRC患者（联合治疗组，=54）或仅接受VEGFRi治疗的患者（VEGFRi组，=32），并评估了其疗效和安全性。我们还通过单细胞和空间转录组数据研究了MSS CRC肿瘤微环境（TME）的免疫特征，并开发了一种可用于预测接受免疫治疗的MSS CRC患者临床结局的MSS CRC免疫细胞相关特征（MCICRS），并在我们的内部队列中进行了验证。与单纯使用VEGFRi相比，抗PD-1抗体与VEGFRi联合使用具有更长的生存获益（中位无进展生存期：4.4个月对2.0个月，=0.0024；中位总生存期：10.2个月对5.2个月，=0.0038），且不良事件发生率相似。通过单细胞和空间转录组分析，我们确定了十种富含MSS CRC的免疫细胞类型及其空间分布，包括初始CD4 T细胞、调节性CD4 T细胞、CD4 Th17细胞、耗竭性CD8 T细胞、细胞毒性CD8 T细胞、增殖性CD8 T细胞、自然杀伤（NK）细胞、浆细胞以及经典单核细胞和中间单核细胞。基于系统的荟萃分析和十种机器学习算法，我们获得了MCICRS，这是MSS CRC患者预后的独立危险因素。进一步分析表明，低MCICRS组具有更高的免疫细胞浸润和免疫相关通路激活，因此与泛癌免疫治疗的卓越疗效显著相关。更重要的是，MCICRS在接受免疫治疗的MSS CRC患者中的预测价值也在内部队列中得到了验证。抗PD-1抗体联合VEGFRi在MSS CRC中显示出更好的临床获益，且毒性可控。MCICRS可作为一种强大且有前景的工具，用于预测接受免疫治疗的个体MSS CRC患者的临床结局。
