Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Mod Pathol. 2023 Sep;36(9):100223. doi: 10.1016/j.modpat.2023.100223. Epub 2023 May 25.
Early detection and treatment of invasive carcinoma arising in association with intraductal papillary mucinous neoplasm (IPMN), which is biologically and (epi)genetically distinct from conventional pancreatic ductal adenocarcinoma, provide an opportunity to improve the prognosis of this lethal disease. Despite the successful application of programmed death (ligand) 1 (PD-[L]1)-blocking strategies in numerous cancers, the immune microenvironment of IPMN with associated invasive carcinoma remains elusive. Here, we investigated CD8 T cells, CD68 macrophages, PD-L1, and V-domain immunoglobulin suppressor of T-cell activation (VISTA) in 60 patients with IPMN with associated invasive carcinoma using immunohistochemistry, explored their correlations with clinicopathologic variables and prognosis, and compared them with those in 76 patients with IPMN without invasive carcinoma (60 low-grade and 16 high-grade lesions). Using antibodies against CD8, CD68, and VISTA, we evaluated tumor-infiltrating immune cells in 5 high-power fields (×400) and calculated the corresponding mean counts. PD-L1 with a combined positive score of ≥1 was regarded as positive, and VISTA expression on tumor cells (TCs) was deemed positive when ≥1% of TCs showed membranous/cytoplasmic staining. A reduction of CD8 T cells and an increase of macrophages were observed during carcinogenesis. Positive PD-L1 combined positive score and VISTA expression on TCs were 13% and 11% in the intraductal component of IPMN with associated invasive carcinoma, 15% and 12% in the associated invasive carcinoma, and 6% and 4% in IPMN without an invasive carcinoma, respectively. Interestingly, the PD-L1 positivity rate was the highest in a subset of associated invasive carcinomas (predominantly gastric-type-derived) and was associated with higher counts of CD8 T cells, macrophages, and VISTA immune cells. Accumulation of VISTA immune cells was observed in the intraductal component of IPMN with associated invasive carcinoma compared with that of low-grade IPMN, whereas in intestinal-type IPMN with associated invasive carcinoma, the number of these cells decreased during the transition from the intraductal component to the associated invasive carcinoma. Survival analysis revealed that a higher number of macrophages predicted poorer prognosis. In conclusion, our results might help in individualized immunotherapeutic strategies for these patients.
早期发现与导管内乳头状黏液性肿瘤（IPMN）相关的浸润性癌，并进行治疗，为改善这种致命疾病的预后提供了机会。尽管程序性死亡（配体）1（PD-L1）阻断策略在许多癌症中的应用取得了成功，但与浸润性癌相关的 IPMN 的免疫微环境仍然难以捉摸。在这里，我们使用免疫组织化学方法研究了 60 例伴有浸润性癌的 IPMN 患者的 CD8 T 细胞、CD68 巨噬细胞、PD-L1 和 V 域免疫球蛋白抑制 T 细胞活化（VISTA），并探讨了它们与临床病理变量和预后的相关性，并将其与 76 例无浸润性癌的 IPMN 患者（60 例低级别和 16 例高级别病变）进行了比较。我们使用针对 CD8、CD68 和 VISTA 的抗体，在 5 个高倍视野（×400）中评估了肿瘤浸润免疫细胞，并计算了相应的平均计数。将 PD-L1 的联合阳性评分≥1 视为阳性，当≥1%的肿瘤细胞（TCs）显示膜/细胞质染色时，将 VISTA 在 TCs 上的表达视为阳性。在癌变过程中，我们观察到 CD8 T 细胞减少和巨噬细胞增加。在伴有浸润性癌的 IPMN 的导管内成分中，PD-L1 联合阳性评分和 TCs 上的 VISTA 表达分别为 13%和 11%，在相关的浸润性癌中分别为 15%和 12%，在无浸润性癌的 IPMN 中分别为 6%和 4%。有趣的是，PD-L1 阳性率在一部分相关浸润性癌（主要是胃型衍生）中最高，与 CD8 T 细胞、巨噬细胞和 VISTA 免疫细胞的计数较高有关。与低级别 IPMN 相比，在伴有浸润性癌的 IPMN 的导管内成分中观察到 VISTA 免疫细胞的积累，而在肠型伴有浸润性癌的 IPMN 中，这些细胞的数量在从导管内成分到相关浸润性癌的转变过程中减少。生存分析表明，巨噬细胞数量较多预示着预后较差。总之，我们的结果可能有助于为这些患者制定个体化的免疫治疗策略。
