Tumor Microenvironment Immune Response in Pancreatic Ductal Adenocarcinoma Patients Treated With Neoadjuvant Therapy
Tumor Microenvironment Immune Response in Pancreatic Ductal Adenocarcinoma Patients Treated With Neoadjuvant Therapy
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DOI：
10.1093/jnci/djaa073
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发表时间：
2021-02-01
影响因子：
10.3
通讯作者：
Ferrone, Cristina R.
中科院分区：
文献类型：
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作者：
Michelakos, Theodoros;Cai, Lei;Ferrone, Cristina R.
背景：新辅助剂亚叶酸、氟尿嘧啶、伊立替康和奥沙利铂(FOLFIRINOX)和放化疗已被用于降低交界性和局部晚期胰腺导管腺癌(PDAC)的分期。目前尚不清楚新辅助治疗诱导的肿瘤免疫反应是否有助于提高生存率。因此，我们评估了新辅助治疗是否诱导了对PDAC的免疫反应。方法：收集马萨诸塞州总医院1998-2016年间手术切除的PDAC的临床病理变量。新辅助方案包括FOLFIRINOX加或不加放化疗组、质子化疗组(25GY)、光子化疗组(50.4GY)或不加新辅助组。采用免疫组织化学方法检测人类白细胞抗原(HL A)I、II类分子的表达及免疫细胞(CD+、FoxP3(+)、CD8(+)、颗粒酶B+细胞、M2巨噬细胞)的表达情况，并与临床病理参数进行相关性分析。比较不同新辅助治疗方案的抗肿瘤免疫应答。所有的统计检验都是双侧的。结果：共纳入248例慢性阻塞性肺疾病患者。中位年龄为岁，女性占50.0%。在FOLFIRINOX队列中，人类白细胞抗原A缺陷的发生率较低(P=0.006)。PHOTON组的HL AⅡ类分子表达最低，质子组最高(P=0.02)。FOLFIRINOX组CD8(+)细胞浸润率最高(P<；.001)。FOLFIRINOX组和质子组的CD4(+)细胞密度最高，FoxP3(+)细胞密度最低。治疗初治组M2巨噬细胞密度显著高于未治疗组(P<；.001)，其中致密的M2巨噬细胞浸润是总体生存不良的独立预测因素。结论：新辅助剂FOLFIRINOX加或不加放化疗均可引起肿瘤微环境的免疫学改变。减少HLAA缺陷，提高CD8(+)细胞密度，降低T调节细胞和M2巨噬细胞密度。因此，新辅助FOLFIRINOX治疗可能受益于与检查点抑制剂的联合治疗，这可以增强患者的抗肿瘤免疫反应。
Background: Neoadjuvant folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) and chemoradiation have been used to downstage borderline and locally advanced pancreatic ductal adenocarcinoma (PDAC). Whether neoadjuvant therapy-induced tumor immune response contributes to the improved survival is unknown. Therefore, we evaluated whether neoadjuvant therapy induces an immune response towards PDAC. Methods: Clinicopathological variables were collected for surgically resected PDACs at the Massachusetts General Hospital (1998-2016). Neoadjuvant regimens included FOLFIRINOX with or without chemoradiation, proton chemoradiation (25 Gy), photon chemoradiation (50.4 Gy), or no neoadjuvant therapy. Human leukocyte antigen (HLA) class I and II expression and immune cell infiltration (CD+, FoxP3(+), CD8(+), granzyme B+ cells, and M2 macrophages) were analyzed immunohistochemically and correlated with clinicopathologic variables. The antitumor immune response was compared among neoadjuvant therapy regimens. All statistical tests were 2-sided. Results: Two hundred forty-eight PDAC patients were included. The median age was 64 years and 50.0% were female. HLA-A defects were less frequent in the FOLFIRINOX cohort (P = .006). HLA class II expression was lowest in photon and highest in proton patients (P = .02). The FOLFIRINOX cohort exhibited the densest CD8(+) cell infiltration (P < .001). FOLFIRINOX and proton patients had the highest CD4(+) and lowest T regulatory (FoxP3(+)) cell density, respectively. M2 macrophage density was statistically significantly higher in the treatment-naive group (P < .001) in which dense M2 macrophage infiltration was an independent predictor of poor overall survival. Conclusions: Neoadjuvant FOLFIRINOX with or without chemoradiation may induce immunologically relevant changes in the tumor microenvironment. It may reduce HLAA defects, increase CD8(+) cell density, and decrease T regulatory cell and M2 macrophage density. Therefore, neoadjuvant FOLFIRINOX therapy may benefit from combinations with checkpoint inhibitors, which can enhance patients' antitumor immune response.