Systemic Immune Activity Predicts Overall Survival in Treatment-Naïve Patients with Metastatic Pancreatic Cancer.
Systemic Immune Activity Predicts Overall Survival in Treatment-Naïve Patients with Metastatic Pancreatic Cancer.
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DOI：
10.1158/1078-0432.ccr-15-1732
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发表时间：
2016-05-15
期刊：
影响因子：
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通讯作者：
Lesinski GB
中科院分区：
文献类型：
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作者：
Farren MR;Mace TA;Geyer S;Mikhail S;Wu C;Ciombor K;Tahiri S;Ahn D;Noonan AM;Villalona-Calero M;Bekaii-Saab T;Lesinski GB
胰腺导管腺癌（PDAC）是一种侵袭性癌症，5年生存率<7%，并且大多数治疗方法最终难以治疗。迄今为止，尚未对初治患者进行全面的疾病相关免疫因素评估。我们假设全身免疫学生物标志物可以预测未经治疗的PDAC患者的总生存期（OS）。从73名先前未经治疗的转移性PDAC患者中采集外周血。进行了广泛的免疫学分析，以评估OS与可溶性血浆生物标志物水平或通过流式细胞术测量的详细免疫细胞表型之间的关系。较高的免疫抑制细胞因子IL-6和IL-10基线水平与较差的OS密切相关（分别为p=0.008和0.026; HR分别为1.16和1.28），而较高水平的单核细胞趋化因子MCP-1与显著较长的OS相关（p=0.045; HR=0.69）。具有更大比例的抗原经历的T细胞（CD 45 RO+）的患者具有更长的OS（分别为CD 4 p=0.032; CD 8 p=0.036; HR=0.36和0.61）。虽然T细胞检查点分子CTLA-4在CD 8 + T细胞上的更高表达与显著更短的OS相关（p=0.020; HR=1.53），但当在CD 4 + T细胞上表达时，TIM 3分子与存活率呈正相关（p=0.046; HR=0.62）。这些数据支持基线免疫状态可预测PDAC病程和患者总体生存率的假设。据我们所知，这项工作代表了迄今为止最大的队列和最全面的未经治疗的转移性PDAC患者的免疫谱。
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a 5-year survival rate <7% and is ultimately refractory to most treatments. To date, an assessment of immunologic factors relevant to disease has not been comprehensively performed for treatment naïve patients. We hypothesized that systemic immunologic biomarkers could predict overall survival (OS) in treatment naïve PDAC patients. Peripheral blood was collected from 73 patients presenting with previously untreated metastatic PDAC. Extensive immunologic profiling was conducted to assess relationships between OS and the level of soluble plasma biomarkers or detailed immune cell phenotypes as measured by flow cytometry. Higher baseline levels of the immunosuppressive cytokines IL-6 and IL-10 were strongly associated with poorer OS (p=0.008 and 0.026, respectively; HR=1.16 and 1.28, respectively), while higher levels of the monocyte chemoattractant MCP-1 were associated with significantly longer OS (p=0.045; HR=0.69). Patients with a greater proportion of antigen-experienced T cells (CD45RO+) had longer OS (CD4 p=0.032; CD8 p=0.036; HR=0.36 and 0.61, respectively). While greater expression of the T cell checkpoint molecule CTLA-4 on CD8+ T cells was associated with significantly shorter OS (p=0.020; HR=1.53), the TIM3 molecule had a positive association with survival when expressed on CD4+ T cells (p=0.046; HR=0.62). These data support the hypothesis that baseline immune status predicts PDAC disease course and overall patient survival. To our knowledge, this work represents the largest cohort and most comprehensive immune profiling of treatment-naïve metastatic PDAC patients to date.