Karamitopoulou Eva, Wenning Anna Silvia, Acharjee Animesh, Zlobec Inti, Aeschbacher Pauline, Perren Aurel, Gloor Beat
Institute for Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
Department of Visceral Surgery, Insel University Hospital, University of Bern, Bern, Switzerland.
Gut. 2023 Aug;72(8):1523-1533. doi: 10.1136/gutjnl-2022-329371. Epub 2023 Feb 15.
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); CD45PanCK (leucocytes) and PanCKCD45 (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 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.
大多数胰腺导管腺癌（PDAC）患者在切除术后会复发。在此，我们研究PDAC复发的空间组织化免疫决定因素。
将PDAC（n = 284；发现队列）根据复发部位分类为肝脏（n = 93/33%）、肺（n = 49/17%）、局部（n = 31/11%）、腹膜（n = 38/13%）和无复发（n = 73/26%）。通过荧光成像确定空间区室为：全细胞角蛋白（PanCK）/CD45（肿瘤细胞）；CD45/PanCK（白细胞）和PanCK/CD45（基质细胞），随后对免疫途径靶点进行转录组分析（72个基因）和蛋白质组分析（51种蛋白质）。整合了来自下一代测序（n = 194）的结果。最后，每组10个肿瘤通过多重免疫荧光进行免疫表型分析。同时检测了一个验证队列（n = 109）。
无复发的PDAC显示出高免疫原性、适应性免疫反应，并且富含促炎趋化因子、颗粒酶B和α平滑肌肌动蛋白成纤维细胞。有肝脏和/或腹膜复发的PDAC显示出低免疫原性、干性表型和固有免疫反应，而有腹膜转移的PDAC还富含FAP成纤维细胞。有局部和/或肺复发的PDAC显示出γ干扰素信号传导以及混合的适应性和固有免疫反应，但主导免疫细胞群体不同。有局部复发的肿瘤过表达树突状细胞标志物，而有肺复发的肿瘤过表达中性粒细胞标志物。除了无复发组仅存在突变外，未观察到基因差异。无复发组预后最佳，而肝脏和腹膜复发组预后最差。
我们的研究结果表明每个复发组存在不同的炎症/基质反应，这可能影响扩散模式和患者预后。这些发现可能有助于为PDAC的个性化辅助/新辅助治疗及监测策略提供信息，包括免疫治疗方式。
