PURPOSE The IMMUNOSARC trial combined an antiangiogenic agent (sunitinib) with a PD1 inhibitor (nivolumab) in advanced sarcomas. Here, we present the first correlative studies of the soft-tissue sarcoma cohort enrolled in this trial. EXPERIMENTAL DESIGN Formalin-fixed paraffin-embedded and peripheral blood samples were collected at baseline and week 13. Formalin-fixed paraffin-embedded samples were used for transcriptomics and multiplex immunofluorescence, whereas peripheral blood samples were used for multiplexed immunoassays. Flow cytometry and Luminex assays were performed to validate translational findings in tumor-isolated cells and peripheral blood mononuclear cells derived from patients. RESULTS The density of intratumoral CD8+ T cells, measured by multiplexed immunophenotyping, was significantly increased after treatment. This augment was accompanied by the dynamic significant increase in the gene expressions of CD86, CHI3L1, CXCL10, CXCL9, LAG3, and VCAM1 and the decrease in the expression levels of NR4A1. In peripheral blood, 12 proteins were significantly modulated by treatment at week 13. A score integrating the dynamic expression of the 7 genes and the 12 soluble factors separated 2 groups with distinct progression-free survival (PFS): 4.1 months [95% confidence interval, 3.5-not reached (NR)] versus 17 months (95% confidence interval, 12.0-NR), P = 0.014. This molecular score was predictive of PFS when applied to the normalized data determined in the baseline samples. CONCLUSIONS Treatment with sunitinib and nivolumab inflamed the sarcoma microenvironment, increasing CD8+ T-cell density and the expression of several genes/proteins with relevance in the response to PD1 inhibitors. A molecular signature identified two groups of patients with distinct PFS for the combination of antiangiogenics plus PD1 inhibitor therapy.

中文翻译：

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抗血管生成药联合 PD1 抑制剂治疗软组织肉瘤的预测和动态特征：与 IMMUNOSARC 试验相关的相关研究。


目的 IMMUNOSARC 试验将抗血管生成药物 （舒尼替尼） 与 PD1 抑制剂 （纳武利尤单抗） 联合治疗晚期肉瘤。在这里，我们介绍了参加该试验的软组织肉瘤队列的第一批相关研究。实验设计 在基线和第 13 周收集福尔马林固定石蜡包埋和外周血样本。福尔马林固定石蜡包埋的样品用于转录组学和多重免疫荧光，而外周血样品用于多重免疫测定。进行流式细胞术和 Luminex 分析以验证肿瘤分离细胞和来自患者的外周血单核细胞的翻译结果。结果 通过多重免疫表型分析测量的瘤内 CD8 + T 细胞密度在治疗后显著增加。这种增强伴随着 CD86 、 CHI3L1 、 CXCL10 、 CXCL9 、 LAG3 和 VCAM1 基因表达的动态显着增加以及 NR4A1 表达水平的降低。在外周血中，第 13 周时治疗显著调节 12 种蛋白。整合 7 个基因和 12 个可溶性因子的动态表达的评分将具有不同无进展生存期 （PFS） 的 2 组分开：4.1 个月 [95% 置信区间，3.5-未达到 （NR）] 与 17 个月 （95% 置信区间，12.0-NR），P = 0.014。当应用于基线样本中确定的标准化数据时，该分子评分可预测 PFS。结论舒尼替尼和纳武利尤单抗治疗使肉瘤微环境发炎，增加 CD8+ T 细胞密度和几个与 PD1 抑制剂反应相关的基因/蛋白的表达。 一项分子特征确定了两组抗血管生成药物联合 PD1 抑制剂治疗具有不同 PFS 的患者。