Immune impact of neoadjuvant chemo/radio-therapy in the pancreatic cancer microenvironment

Pancreatic ductal adenocarcinoma (PDAC) has dismal five-year survival (<9%). We examined the impact of neoadjuvant FOLFIRINOX alone or in combination with radiation therapy (conventional radiotherapy, XRT, or stereotactic body radiotherapy, SBRT) on immunologically relevant genes in the PDAC tumor microenvironment (TME). We hypothesize conventional therapies may induce immune alterations in the TME that can be leveraged to enhance the efficacy of immunotherapy in PDAC. PDAC patients who underwent upfront surgical resection or who received neoadjuvant FOLFIRINOX with or without neoadjuvant radiotherapy followed by surgical resection were selected for study. The expression of 730 immunologically relevant transcripts was quantitated using the Nanostring PanCancer immune profiling panel (Platform GPL19965). This analysis identified189 genes that were differentially expressed at the RNA level on the basis of neoadjuvant therapy. On average specimens were obtained 6.6-17.0 weeks after the conclusion of neoadjuvant therapy, depending on treatment group. These data provide insight into the immunological effects of standard of care neoadjuvant therapy for resectable/borderline-resectable PDAC. This work provides data to guide strategic new combination therapies for pancreatic cancer. Gene expression profiles were generated on a total of 24 individuals who underwent surgical resection for PDAC at Emory University using the Nanostring PanCancer Immune Profiling Panel (XT-CSO-HIP1-12; Platform GPL19965). Patients who received upfront surgical resection (no neoadjuvant therapy) served as an overall control group for comparison purposes (n=6). Patients who received neoadjuvant FOLFIRINOX served as a secondary comparator-control (n=6). These two groups were compared to each other, and to patients who received neoadjuvant FOLFIRINOX and neoadjuvant radiation therapy (steriotactic body radiotherapy or conventional external beam radiotherapy, n=6 each). Following image acquisition mRNA counts were extracted from raw RCC files using nSolver analysis software v3.0 (Nanostring). Data was then normalized using nSolver.

胰腺导管腺癌（Pancreatic ductal adenocarcinoma, PDAC）的五年生存率极低（不足9%）。本研究探讨了单独使用新辅助FOLFIRINOX方案，或联合放疗（常规放疗，即conventional radiotherapy，缩写XRT；或体部立体定向放疗，即stereotactic body radiotherapy，缩写SBRT）对胰腺导管腺癌肿瘤微环境（Tumor Microenvironment, TME）中免疫相关基因的影响。我们提出假设：常规治疗可诱导肿瘤微环境发生免疫改变，借此可提升胰腺导管腺癌免疫治疗的疗效。本研究纳入两类患者：一类接受直接手术切除，另一类接受新辅助FOLFIRINOX方案联合或不联合新辅助放疗，随后行手术切除。采用Nanostring泛癌免疫分析试剂盒（平台GPL19965）对730个免疫相关转录本的表达水平进行定量检测。本分析共鉴定出189个在新辅助治疗背景下存在RNA水平差异表达的基因。根据治疗分组的不同，标本采集时间为新辅助治疗结束后6.6~17.0周不等。本数据集为可切除/临界可切除胰腺导管腺癌的标准治疗新辅助方案的免疫学效应提供了见解，同时为胰腺癌新型联合治疗策略的开发提供了数据支持。本研究共纳入24名在埃默里大学接受胰腺导管腺癌手术切除的患者，采用Nanostring泛癌免疫分析试剂盒（XT-CSO-HIP1-12；平台GPL19965）生成基因表达谱。其中，接受直接手术切除（未接受新辅助治疗）的患者作为总体对照组（n=6）；接受新辅助FOLFIRINOX方案的患者作为次要对照队列（n=6）。将上述两个队列分别与接受新辅助FOLFIRINOX方案联合新辅助放疗（体部立体定向放疗或常规外照射放疗，每组n=6）的患者进行对比分析。图像采集完成后，使用nSolver分析软件v3.0（Nanostring）从原始RCC文件中提取mRNA计数数据，随后通过nSolver完成数据标准化。