Karamitopoulou Eva, Andreou Andreas, Pahud de Mortanges Aurélie, Tinguely Marianne, Gloor Beat, Perren Aurel
Institute of Pathology, University of Bern, Bern, Switzerland.
Pathology Institute Enge, Zurich, Switzerland.
Cancer Immunol Res. 2021 Dec;9(12):1439-1450. doi: 10.1158/2326-6066.CIR-21-0144. Epub 2021 Sep 15.
Immunotherapy, including PD-1/PD-L1 agonists, has shown limited efficacy in pancreatic ductal adenocarcinoma (PDAC). We examined the PD-1/PD-L1 expression and immunoarchitectural features by automated morphometric analysis using multiplex immunofluorescence and 118 microsatellite-stable, treatment-naïve, surgically resected PDACs (study cohort). Five microsatellite-instable cases were stained in parallel (MSI cohort). Molecular analysis was additionally performed. An independent PDAC cohort ( = 226) was immunostained for PD-L1 and used as a validation cohort. PD-L1 expression on tumor cells (TC) and/or immune cells (IC) was present in 32% and 30% of the study and validation cohorts, respectively, and assigned into one of four patterns: "adaptive-1" (TC: 0, IC > 1%), "adaptive-2" (TC > 1% to < 25%, IC > 1%), "constitutive" (TC ≥ 25%, IC: 0), and "combined" (TC ≥ 25%, IC > 1%). "Constitutive" tumors were characterized by reduced numbers of all ICs and poor outcome. In contrast, "adaptive-1" tumors exhibited abundant T cells, including high counts of cytotoxic CD3CD8 and PD-1CD3CD8 cells, but low counts of PD-L1CD3CD8 cells and associated with the best outcome. "Adaptive-2" tumors displayed higher proportions of PD-L1CD3CD8 T cells and tumor-associated macrophages (CD68 and CD68CD206) compared with "adaptive-1" tumors. In the "combined" pattern, extensive PD-L1 expression on TCs was accompanied by increased numbers of T cells and improved overall survival. ICs were closer to PD-L1 than to PD-L1 PDAC cells. and alterations tended to be more frequent in PD-L1 tumors. The 5 MSI cases were PD-L1 The distinct PD-1/PD-L1-associated immunoarchitectural patterns underpin the heterogeneity of the immunologic responses and might be used to inform patient outcomes and therapeutic decisions in pancreatic cancer.
免疫疗法，包括PD-1/PD-L1激动剂，在胰腺导管腺癌（PDAC）中显示出有限的疗效。我们使用多重免疫荧光和118例微卫星稳定、未经治疗、手术切除的PDAC（研究队列），通过自动形态计量分析检查了PD-1/PD-L1表达和免疫结构特征。另外对5例微卫星不稳定病例进行了平行染色（微卫星不稳定队列）。还进行了分子分析。一个独立的PDAC队列（n = 226）进行了PD-L1免疫染色，并用作验证队列。研究队列和验证队列中分别有32%和30%的肿瘤细胞（TC）和/或免疫细胞（IC）表达PD-L1，并分为四种模式之一：“适应性-1”（TC：0，IC > 1%）、“适应性-2”（TC > 1%至< 25%，IC > 1%）、“组成性”（TC≥25%，IC：0）和“组合性”（TC≥25%，IC > 1%）。“组成性”肿瘤的特征是所有IC数量减少且预后不良。相比之下，“适应性-1”肿瘤表现出丰富的T细胞，包括高计数的细胞毒性CD3CD8和PD-1CD3CD8细胞，但PD-L1CD3CD8细胞计数低，且预后最佳。与“适应性-1”肿瘤相比，“适应性-2”肿瘤显示出更高比例的PD-L1CD3CD8 T细胞和肿瘤相关巨噬细胞（CD68和CD68CD206）。在“组合性”模式中，TC上广泛的PD-L1表达伴随着T细胞数量增加和总生存期改善。IC比PD-L1阴性的PDAC细胞更接近PD-L1阳性细胞。并且KRAS和NRAS改变在PD-L1阳性肿瘤中往往更频繁。5例微卫星不稳定病例为PD-L1阳性。不同的PD-1/PD-L1相关免疫结构模式是免疫反应异质性的基础，可能用于指导胰腺癌患者的预后和治疗决策。
