Schroeder Brett A, Zhang Yuzheng, Smythe Kimberly S, Desai Parth, Thomas Anish, Viveiros Pedro, Alexiev Borislav A, Obeidin Farres, Chen Eleanor Y, Cranmer Lee D, Wagner Michael J, Jones Robin L, Campbell Jean S, Pierce Robert H, He Qianchuan, Pollack Seth M
National Cancer Institute, National Institutes of Health, Bethesda, MD 20829, USA.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Cancers (Basel). 2022 Mar 2;14(5):1290. doi: 10.3390/cancers14051290.
Patients with metastatic soft tissue sarcoma (STS) have a poor prognosis and few available systemic treatment options. Trabectedin is currently being investigated as a potential adjunct to immunotherapy as it has been previously shown to kill tumor-associated macrophages. In this retrospective study, we sought to identify biomarkers that would be relevant to trials combining trabectedin with immunotherapy. We performed a single-center retrospective study of sarcoma patients treated with trabectedin with long-term follow-up. Multiplex gene expression analysis using the NanoString platform was assessed, and an exploratory analysis using the lasso-penalized Cox regression and kernel association test for survival (MiRKAT-S) methods investigated tumor-associated immune cells and correlated their gene signatures to patient survival. In total, 147 sarcoma patients treated with trabectedin were analyzed, with a mean follow-up time of 5 years. Patients with fewer prior chemotherapy regimens were more likely to stay on trabectedin longer (pairwise correlation = -0.17, = 0.04). At 5 years, increased PD-L1 expression corresponded to worse outcomes (HR = 1.87, = 0.04, = 0.199). Additionally, six immunologic gene signatures were associated with up to 7-year survival by MiRKAT-S, notably myeloid-derived suppressor cells ( = 0.023, = 0.058) and M2 macrophages ( = 0.03, = 0.058). We found that the number of chemotherapy regimens prior to trabectedin negatively correlated with the number of trabectedin cycles received, suggesting that patients may benefit from receiving trabectedin earlier in their therapy course. The correlation of trabectedin outcomes with immune cell infiltrates supports the hypothesis that trabectedin may function as an immune modulator and supports ongoing efforts to study trabectedin in combination with immunotherapy. Furthermore, tumors with an immunosuppressive microenvironment characterized by macrophage infiltration and high PD-L1 expression were less likely to benefit from trabectedin, which could guide clinicians in future treatment decisions.
转移性软组织肉瘤（STS）患者预后较差，可用的全身治疗方案有限。曲贝替定目前正在作为免疫治疗的潜在辅助药物进行研究，因为此前已证明它能杀死肿瘤相关巨噬细胞。在这项回顾性研究中，我们试图确定与曲贝替定联合免疫治疗试验相关的生物标志物。我们对接受曲贝替定治疗并进行长期随访的肉瘤患者进行了单中心回顾性研究。使用NanoString平台进行了多重基因表达分析，并使用套索惩罚Cox回归和生存核关联检验（MiRKAT-S）方法进行探索性分析，以研究肿瘤相关免疫细胞，并将其基因特征与患者生存情况相关联。总共分析了147例接受曲贝替定治疗的肉瘤患者，平均随访时间为5年。既往化疗方案较少的患者更有可能接受曲贝替定治疗的时间更长（成对相关性=-0.17，P=0.04）。在5年时，PD-L1表达增加与较差的预后相关（风险比=1.87，P=0.04，C指数=0.199）。此外，通过MiRKAT-S分析，六种免疫基因特征与长达7年的生存率相关，特别是髓源性抑制细胞（P=0.023，C指数=0.058）和M2巨噬细胞（P=0.03，C指数=0.058）。我们发现，曲贝替定治疗前的化疗方案数量与接受曲贝替定的周期数呈负相关，这表明患者可能在治疗过程中更早接受曲贝替定治疗会受益。曲贝替定治疗结果与免疫细胞浸润的相关性支持了曲贝替定可能作为免疫调节剂发挥作用的假设，并支持正在进行的曲贝替定联合免疫治疗的研究工作。此外，具有以巨噬细胞浸润和高PD-L1表达为特征的免疫抑制微环境的肿瘤从曲贝替定治疗中获益的可能性较小，这可为临床医生未来的治疗决策提供指导。
