大多数胰管腺癌（PDAC）患者在切除后会出现复发。因此，我们研究了PDAC复发的空间组织免疫决定因素。在发现队列（n=284）中，PDAC被分类为肝脏（n=93/33%）、肺（n=49/17%）、局部（n=31/11%）、腹膜（n=38/13%）和无复发（n=73/26%）。我们通过荧光成像鉴定空间区域为泛细胞角蛋白（PanCK）+CD45-（肿瘤细胞）、CD45+PanCK-（白细胞）和PanCK-CD45-（间质细胞），并对免疫通路靶点进行基因转录组（72个基因）和蛋白质组（51个蛋白）分析。接下来整合了194个下一代测序数据。最后，每组选取10个瘤进行多重免疫荧光分析。平行检查了一个验证队列（n=109）。无复发PDAC表现出高免疫原性、适应性免疫反应，并富含促炎性趋化因子、粒肽酶B和α-平滑肌肌动蛋白+成纤维细胞。肝脏和/或腹膜复发的PDAC表现出低免疫原性、干细胞特性和先天免疫反应，而腹膜转移的PDAC还富含FAP+成纤维细胞。局部和/或肺复发的PDAC表现出干扰素-γ信号和混合适应性和先天性免疫反应，但具有不同的免疫细胞群。具有局部复发的肿瘤过量表达树突状细胞标记物，而具有肺复发的肿瘤过量表达嗜中性粒细胞标记物。除了无复发组中独特的RNF43突变外，未见遗传差异。无复发组表现出最佳的预后，而肝脏和腹膜复发组则表现最差。我们的研究结果表明，每个复发组中存在着明显的炎性/间质反应，可能影响传播模式和患者预后。这些发现有助于制定个性化的辅助/新辅助和监测策略，包括免疫治疗。©作者（或其雇主）（2023）。不得商业再利用。请参阅权利和权限。由BMJ出版。

Most patients with pancreatic ductal adenocarcinoma (PDAC) will experience recurrence after resection. Here, we investigate spatially organised immune determinants of PDAC recurrence.PDACs (n=284; discovery cohort) were classified according to recurrence site as liver (n=93/33%), lung (n=49/17%), local (n=31/11%), peritoneal (n=38/13%) and no-recurrence (n=73/26%). Spatial compartments were identified by fluorescent imaging as: pancytokeratin (PanCK)+CD45- (tumour cells); CD45+PanCK- (leucocytes) and PanCK-CD45- (stromal cells), followed by transcriptomic (72 genes) and proteomic analysis (51 proteins) for immune pathway targets. Results from next-generation sequencing (n=194) were integrated. Finally, 10 tumours from each group underwent immunophenotypic analysis by multiplex immunofluorescence. A validation cohort (n=109) was examined in parallel.No-recurrent PDACs show high immunogenicity, adaptive immune responses and are rich in pro-inflammatory chemokines, granzyme B and alpha-smooth muscle actin+ fibroblasts. PDACs with liver and/or peritoneal recurrences display low immunogenicity, stemness phenotype and innate immune responses, whereas those with peritoneal metastases are additionally rich in FAP+ fibroblasts. PDACs with local and/or lung recurrences display interferon-gamma signalling and mixed adaptive and innate immune responses, but with different leading immune cell population. Tumours with local recurrences overexpress dendritic cell markers whereas those with lung recurrences neutrophilic markers. Except the exclusive presence of RNF43 mutations in the no-recurrence group, no genetic differences were seen. The no-recurrence group exhibited the best, whereas liver and peritoneal recurrences the poorest prognosis.Our findings demonstrate distinct inflammatory/stromal responses in each recurrence group, which might affect dissemination patterns and patient outcomes. These findings may help to inform personalised adjuvant/neoadjuvant and surveillance strategies in PDAC, including immunotherapeutic modalities.© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.