Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death with a median survival time of 6–12 months. Most patients present with disseminated disease and the majority are offered palliative chemotherapy. With no approved treatment modalities for patients who progress on chemotherapy, we explored the effects of long-term gemcitabine administration on the tumor microenvironment to identify potential therapeutic options for chemorefractory PDAC. Using a combination of mouse models, primary cell line–derived xenografts, and established tumor cell lines, we first evaluated chemotherapy-induced alterations in the tumor secretome and immune surface proteins by high throughput proteomic arrays. In addition to enhancing antigen presentation and immune checkpoint expression, gemcitabine consistently increased the synthesis of CCL/CXCL chemokines and TGFβ-associated signals. These secreted factors altered the composition of the tumor stroma, conferring gemcitabine resistance to cancer-associated fibroblasts in vitro and further enhancing TGFβ1 biosynthesis. Combined gemcitabine and anti-PD-1 treatment in transgenic models of murine PDAC failed to alter disease course unless mice also underwent genetic or pharmacologic ablation of TGFβ signaling. In the setting of TGFβ signaling deficiency, gemcitabine and anti-PD-1 led to a robust CD8+ T-cell response and decrease in tumor burden, markedly enhancing overall survival. These results suggest that gemcitabine successfully primes PDAC tumors for immune checkpoint inhibition by enhancing antigen presentation only following disruption of the immunosuppressive cytokine barrier. Given the current lack of third-line treatment options, this approach warrants consideration in the clinical management of gemcitabine-refractory PDAC. Significance: These data suggest that long-term treatment with gemcitabine leads to extensive reprogramming of the pancreatic tumor microenvironment and that patients who progress on gemcitabine-based regimens may benefit from multidrug immunotherapy. See related commentary by Carpenter et al., [p. 3070][1] Graphical Abstract: . [1]: /lookup/volpage/80/3070?iss=15

中文翻译：

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长期吉西他滨治疗重塑胰腺肿瘤微环境并使鼠癌对联合免疫疗法敏感。

胰腺导管腺癌 (PDAC) 是癌症相关死亡的主要原因，中位生存时间为 6-12 个月。大多数患者患有播散性疾病，大多数患者接受姑息性化疗。由于尚无针对化疗进展患者的批准治疗方式，我们探索了长期吉西他滨给药对肿瘤微环境的影响，以确定化学难治性 PDAC 的潜在治疗选择。使用小鼠模型、原代细胞系衍生的异种移植物和已建立的肿瘤细胞系的组合，我们首先通过高通量蛋白质组阵列评估了化疗诱导的肿瘤分泌组和免疫表面蛋白的改变。除了增强抗原呈递和免疫检查点表达外，吉西他滨持续增加 CCL/CXCL 趋化因子和 TGFβ 相关信号的合成。这些分泌因子改变了肿瘤基质的组成，在体外赋予吉西他滨对癌症相关成纤维细胞的抗性，并进一步增强 TGFβ1 的生物合成。在小鼠 PDAC 转基因模型中，吉西他滨和抗 PD-1 联合治疗未能改变病程，除非小鼠也经历了 TGFβ 信号传导的遗传或药物消融。在 TGFβ 信号传导缺陷的情况下，吉西他滨和抗 PD-1 导致强大的 CD8+ T 细胞反应并降低肿瘤负荷，显着提高总体存活率。这些结果表明，吉西他滨通过仅在免疫抑制细胞因子屏障破坏后增强抗原呈递，成功地引发 PDAC 肿瘤的免疫检查点抑制。鉴于目前缺乏三线治疗选择，这种方法值得在吉西他滨难治性 PDAC 的临床管理中考虑。意义：这些数据表明，吉西他滨的长期治疗会导致胰腺肿瘤微环境的广泛重编程，并且在基于吉西他滨的方案中取得进展的患者可能会受益于多药免疫治疗。参见 Carpenter 等人的相关评论，[p. 3070][1] 图形摘要：这些数据表明，吉西他滨的长期治疗会导致胰腺肿瘤微环境的广泛重编程，并且在基于吉西他滨的方案上取得进展的患者可能会受益于多药免疫治疗。参见 Carpenter 等人的相关评论，[p. 3070][1] 图形摘要：这些数据表明，吉西他滨的长期治疗会导致胰腺肿瘤微环境的广泛重编程，并且在基于吉西他滨的方案上取得进展的患者可能会受益于多药免疫治疗。参见 Carpenter 等人的相关评论，[p. 3070][1] 图形摘要：. [1]：/lookup/volpage/80/3070?iss=15