Sequential Platinum and PARP Inhibition Enhances PD1 Immunotherapy Efficacy in Murine Brca2 Mutated Pancreatic Cancer [RNAseq_1]

Pancreatic ductal adenocarcinoma (PDAC) is a challenging malignancy to treat, but emerging evidence suggests that specific subtypes may respond more favorably to certain therapies. BRCA-mutated PDAC represents a distinct subtype that is particularly sensitive to DNA-damaging therapies. The current standard of care for advanced BRCA-mutated PDAC involves induction platinum-based chemotherapy followed by maintenance therapy with a poly (ADP-ribose) polymerase inhibitor (PARPi). However, the randomized phase III POLO trial, upon which this standard is based, did not demonstrate an improved overall survival in patients who received olaparib compared to those who received placebo, highlighting the need for new therapeutic approaches. Additionally, there is a lack of robust models that recapitulate the tumor microenvironment of BRCA mutated PDAC, limiting the development of next-generation maintenance treatment options. In this study, we developed a syngeneic and immunocompetent mouse model of Brca2-mutated PDAC. The model demonstrated high sensitivity to cisplatin plus gemcitabine, but limited efficacy of PARPi monotherapy. Induction with platinum-based chemotherapy sensitized tumors to PARPi maintenance therapy and promoted an exhausted, T cell-inflamed tumor microenvironment. However, resistance emerged which was associated with CDX2 expression and tumor differentiation. The addition of anti-PD1 treatment to PARPi maintenance enhanced tumor regression and prolonged overall survival. These findings provide preclinical support for ongoing clinical trials investigating immunotherapy with PARPi as a maintenance strategy in homologous recombination-deficient PDAC. Overall design: Bulk RNA sequencing assessing impact of Gemcitabine/Cisplatin or Olaparib in a BRCA2 mutated mouse model

胰腺导管腺癌（Pancreatic ductal adenocarcinoma, PDAC）是一种极具治疗挑战的恶性肿瘤，但日益增多的研究证据表明，特定亚型或许对针对性疗法展现出更优响应。BRCA突变型胰腺导管腺癌（BRCA-mutated PDAC）是一类独特亚型，对DNA损伤类疗法尤为敏感。目前晚期BRCA突变型胰腺导管腺癌的标准治疗方案为：先实施含铂诱导化疗，后续采用聚腺苷二磷酸核糖聚合酶抑制剂（poly (ADP-ribose) polymerase inhibitor, PARPi）进行维持治疗。然而，支撑该标准方案的随机Ⅲ期POLO试验并未证实，相较于安慰剂组，接受奥拉帕利（olaparib）治疗的患者总生存期得到显著改善，这凸显了开发新型治疗策略的迫切需求。此外，当前缺乏能够精准重现BRCA突变型胰腺导管腺癌肿瘤微环境的可靠模型，这限制了下一代维持治疗方案的研发。在本研究中，我们构建了Brca2突变型胰腺导管腺癌的同基因免疫健全小鼠模型。该模型对顺铂（cisplatin）联合吉西他滨（gemcitabine）展现出高敏感性，但PARPi单药治疗的疗效有限。经含铂诱导化疗后，肿瘤对PARPi维持治疗的敏感性得以提升，且肿瘤微环境呈现耗竭性T细胞炎性表型。不过，后续出现了治疗耐药，该耐药与尾型同源框转录因子2（CDX2）表达及肿瘤分化程度相关。在PARPi维持治疗基础上联用抗PD-1（anti-PD1）治疗，可增强肿瘤退缩效果并延长总生存期。上述研究结果为正在开展的临床试验提供了临床前依据，这些试验旨在评估PARPi联合免疫疗法作为同源重组缺陷型胰腺导管腺癌（homologous recombination-deficient PDAC）维持治疗策略的有效性。整体实验设计：采用批量RNA测序（Bulk RNA sequencing）评估吉西他滨/顺铂或奥拉帕利对BRCA2突变型小鼠模型的影响。