Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC), expecting to be the second leading cause of cancer deaths by 2030, resists immune checkpoint therapies due to its immunosuppressive tumor microenvironment (TME). Leukemia inhibitory factor (LIF) is a key target in PDAC, promoting stemness, epithelial–mesenchymal transition (EMT), and therapy resistance. Phase 1 clinical trials showed anti-LIF therapy is safe but with limited efficacy, suggesting better outcomes when combined with chemotherapy, radiotherapy, or immunotherapy.Methods: We assessed the combination of chemotherapy (gemcitabine/nab-paclitaxel) and dual blockade of LIF and PD-L1 on tumor growth and survival in orthotopic and spontaneous PDAC models. Flow cytometry and scRNA-seq were utilized to monitor the antitumor immune response. The role of key immune cells was further confirmed by depleting these immune cells, including CD4, CD8, or inflammatory monocytes.Results: Sequential treatment with chemotherapy (gemcitabine/nab-paclitaxel) and dual blockade of LIF and PD-L1 significantly improved antitumor efficacy compared to monotherapy or dual combinations of these therapies. This chemo/anti-LIF/anti-PD-L1 approach reduced EMT in tumor cells and enhanced the antitumor immune response, primarily through CD8 T cells, as depleting CD8 cells largely abrogated the effect of treatment. This combination therapy also shifted macrophages and dendritic cells towards an antitumor phenotype.Conclusions: The combination of chemotherapy, anti-LIF, and anti-PD-L1 not only targeted tumor cells but also augmented the anti-tumor immune response. These findings strongly support advancing chemo/anti-LIF/anti-PD-L1 combination therapy to clinical trials in PDAC.
背景/目的：胰腺导管腺癌（PDAC）预计到2030年将成为癌症死亡的第二大原因，因其免疫抑制性肿瘤微环境而对免疫检查点疗法产生抵抗。白血病抑制因子（LIF）是PDAC的关键靶点，可促进肿瘤干细胞特性、上皮-间质转化（EMT）及治疗抵抗。一期临床试验显示抗LIF疗法安全性良好但疗效有限，提示其与化疗、放疗或免疫疗法联合应用可能获得更好疗效。 方法：我们在原位及自发性PDAC模型中评估了化疗（吉西他滨/白蛋白结合型紫杉醇）联合LIF与PD-L1双重阻断对肿瘤生长及生存期的影响。采用流式细胞术和单细胞RNA测序监测抗肿瘤免疫反应。通过耗竭CD4、CD8或炎性单核细胞等关键免疫细胞，进一步验证了这些细胞的作用。 结果：与单药治疗或双重联合疗法相比，化疗（吉西他滨/白蛋白结合型紫杉醇）序贯LIF与PD-L1双重阻断能显著提升抗肿瘤疗效。这种化疗/抗LIF/抗PD-L1联合方案降低了肿瘤细胞的EMT水平，并通过CD8 T细胞主要增强了抗肿瘤免疫反应——耗竭CD8细胞可基本消除该治疗效果。该联合疗法还促使巨噬细胞和树突状细胞向抗肿瘤表型转化。 结论：化疗联合抗LIF与抗PD-L1疗法不仅能靶向肿瘤细胞，还能增强抗肿瘤免疫反应。这些发现为推进化疗/抗LIF/抗PD-L1联合疗法进入PDAC临床试验提供了有力支持。
Blockade of LIF and PD-L1 Enhances Chemotherapy in Preclinical PDAC Models
肿瘤(癌症)患者之家