CD47 Blockade as an Adjuvant Immunotherapy for Resectable Pancreatic Cancer.
CD47 Blockade as an Adjuvant Immunotherapy for Resectable Pancreatic Cancer.
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DOI：
10.1158/1078-0432.ccr-17-2283
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发表时间：
2018-03-15
期刊：
影响因子：
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通讯作者：
Bauer TW
中科院分区：
文献类型：
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作者：
Michaels AD;Newhook TE;Adair SJ;Morioka S;Goudreau BJ;Nagdas S;Mullen MG;Persily JB;Bullock TNJ;Slingluff CL Jr;Ravichandran KS;Parsons JT;Bauer TW
接受手术切除和辅助化疗的胰腺导管腺癌（PDAC）患者由于疾病复发（通常在肝脏），预期生存期仅为两年。我们研究了肝脏巨噬细胞在PDAC微转移进展中的作用，以确定可以延长生存期的辅助治疗策略。肝微转移PDAC的小鼠脾脏注射模型与五个患者来源的PDAC肿瘤一起使用。通过以下方式评估肝巨噬细胞对肿瘤生长的影响：1）用脂质体氯膦酸盐注射耗尽裸鼠中的小鼠巨噬细胞，和2）将肿瘤细胞注射到裸鼠与NOD-scid-γ小鼠中。免疫组织化学和流式细胞术用于测量肿瘤细胞上的CD 47（“不要吃我信号”）表达并表征肿瘤微环境中的巨噬细胞。用CD 47阻断抗体进行体外吞噬测定和小鼠实验，以评估肿瘤细胞的巨噬细胞吞噬、肝脏中微转移的进展和小鼠存活率。体内氯膦酸盐耗竭实验和NOD-scid-gamma小鼠实验表明，肝脏巨噬细胞抑制PDAC微转移的进展。5个患者来源的PDAC细胞系表达不同水平的CD 47。在体外吞噬试验中，CD 47阻断抗体以与CD 47受体表面密度相关的方式增加了巨噬细胞对PDAC细胞的清除效率。用CD 47阻断抗体治疗小鼠导致转移性肿瘤进展时间延长和生存期延长。这些发现表明，PDAC手术切除后，抗CD 47抗体的辅助免疫治疗可显著改善患者的结局。
Patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgical resection and adjuvant chemotherapy have an expected survival of only two years due to disease recurrence, frequently in the liver. We investigated the role of liver macrophages in progression of PDAC micrometastases to identify adjuvant treatment strategies that could prolong survival. A murine splenic injection model of hepatic micrometastatic PDAC was used with five patient-derived PDAC tumors. The impact of liver macrophages on tumor growth was assessed by 1) depleting mouse macrophages in nude mice with liposomal clodronate injection, and 2) injecting tumor cells into nude vs. NOD-scid-gamma mice. Immunohistochemistry and flow cytometry were used to measure CD47 (“don’t eat me signal”) expression on tumor cells and characterize macrophages in the tumor microenvironment. In vitro engulfment assays and mouse experiments were performed with CD47-blocking antibodies to assess macrophage engulfment of tumor cells, progression of micrometastases in the liver and mouse survival. In vivo clodronate depletion experiments and NOD-scid-gamma mouse experiments demonstrated that liver macrophages suppress the progression of PDAC micrometastases. Five patient-derived PDAC cell lines expressed variable levels of CD47. In in vitro engulfment assays, CD47-blocking antibodies increased the efficiency of PDAC cell clearance by macrophages in a manner which correlated with CD47 receptor surface density. Treatment of mice with CD47-blocking antibodies resulted in increased time-to-progression of metastatic tumors and prolonged survival. These findings suggest that following surgical resection of PDAC, adjuvant immunotherapy with anti-CD47 antibody could lead to substantially improved outcomes for patients.