Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
J Natl Cancer Inst. 2021 Feb 1;113(2):182-191. doi: 10.1093/jnci/djaa073.
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.
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 (CD4+, 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.
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-naïve group (P < .001) in which dense M2 macrophage infiltration was an independent predictor of poor overall survival.
Neoadjuvant FOLFIRINOX with or without chemoradiation may induce immunologically relevant changes in the tumor microenvironment. It may reduce HLA-A 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.
新辅助氟尿嘧啶、亚叶酸钙、伊立替康和奥沙利铂（FOLFIRINOX）联合放化疗已被用于降期交界性和局部进展期胰腺导管腺癌（PDAC）。新辅助治疗诱导的肿瘤免疫反应是否有助于提高生存率尚不清楚。因此，我们评估了新辅助治疗是否会引起针对 PDAC 的免疫反应。
收集了马萨诸塞州综合医院（1998-2016 年）手术切除的 PDAC 的临床病理变量。新辅助方案包括 FOLFIRINOX 联合或不联合放化疗、质子放化疗（25Gy）、光子放化疗（50.4Gy）或无新辅助治疗。用人白细胞抗原（HLA）I 类和 II 类表达和免疫细胞浸润（CD4+、FoxP3+、CD8+、颗粒酶 B+细胞和 M2 巨噬细胞）进行免疫组化分析，并与临床病理变量相关联。比较了新辅助治疗方案之间的抗肿瘤免疫反应。所有统计检验均为双侧。
纳入 248 例 PDAC 患者。中位年龄为 64 岁，50.0%为女性。FOLFIRINOX 组 HLA-A 缺陷较少（P =.006）。HLA II 类表达在光子患者中最低，在质子患者中最高（P =.02）。FOLFIRINOX 组 CD8+细胞浸润最密集（P <.001）。FOLFIRINOX 和质子组的 CD4+细胞密度最高，T 调节（FoxP3+）细胞密度最低。未经治疗组的 M2 巨噬细胞密度明显更高（P <.001），其中密集的 M2 巨噬细胞浸润是总生存不良的独立预测因素。
新辅助 FOLFIRINOX 联合或不联合放化疗可能会引起肿瘤微环境中的免疫相关变化。它可能会减少 HLA-A 缺陷，增加 CD8+细胞密度，并减少 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联合使用，这可以增强患者的抗肿瘤免疫反应。
