Long-Term Gemcitabine Treatment Reshapes the Pancreatic Tumor Microenvironment and Sensitizes Murine Carcinoma to Combination Immunotherapy.
Long-Term Gemcitabine Treatment Reshapes the Pancreatic Tumor Microenvironment and Sensitizes Murine Carcinoma to Combination Immunotherapy.
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DOI：
10.1158/0008-5472.can-19-2959
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发表时间：
2020-08-01
期刊：
影响因子：
11.2
通讯作者：
Rana A
中科院分区：
文献类型：
--
作者：
Principe DR;Narbutis M;Kumar S;Park A;Viswakarma N;Dorman MJ;Kamath SD;Grippo PJ;Fishel ML;Hwang RF;Thummuri D;Underwood PW;Munshi HG;Trevino JG;Rana A
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。大多数患者表现为播散性疾病，大多数患者接受姑息性化疗。由于没有批准的治疗方式用于化疗进展的患者，我们探索了长期吉西他滨对肿瘤微环境的影响，以确定化疗难治性PDAC的潜在治疗选择。使用小鼠模型、原代细胞系来源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学阵列评估了肿瘤分泌组和免疫表面蛋白的化疗诱导的改变。除了增强抗原呈递和免疫检查点表达外，吉西他滨还持续增加CCL/CXCL趋化因子和TGFβ相关信号的合成。这些分泌的因子改变了肿瘤间质的组成，在体外赋予癌症相关成纤维细胞吉西他滨抗性，并进一步增强TGFβ1的生物合成。在鼠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TGFβ信号传导的遗传或药理学消融。在TGFβ信号传导缺陷的情况下，吉西他滨和抗PD-1导致稳健的CD 8 + T细胞应答和肿瘤负荷降低，显著提高总生存期。这些结果表明，吉西他滨通过仅在免疫抑制性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，这种方法值得考虑在吉西他滨难治性PDAC的临床管理。
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 on the tumor microenvironment in order to identify potential therapeutic options for chemo-refractory 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.