Transforming growth factor-b (TGFb) plays pleiotropic roles in pancreatic cancer, including promoting metastasis, attenuating CD8 T-cell activation, and enhancing myofibroblast differentiation and deposition of extracellular matrix. However, single-agent TGFb inhibition has shown limited efficacy against pancreatic cancer in mice or humans. We evaluated the TGFβ-blocking antibody NIS793 in combination with gemcitabine/nanoparticle (albumin-bound)-paclitaxel or FOLFIRINOX (folinic acid [FOL], 5-fluorouracil [F], irinotecan [IRI] and oxaliplatin [OX]) in orthotopic pancreatic cancer models. Single-cell RNA sequencing and immunofluorescence were used to evaluate changes in tumor cell state and the tumor microenvironment. Blockade of TGFβ with chemotherapy reduced tumor burden in poorly immunogenic pancreatic cancer, without affecting the metastatic rate of cancer cells. Efficacy of combination therapy was not dependent on CD8 T cells, because response to TGFβ blockade was preserved in CD8-depleted or recombination activating gene 2 (RAG2) mice. TGFβ blockade decreased total α-smooth muscle actin–positive fibroblasts but had minimal effect on fibroblast heterogeneity. Bulk RNA sequencing on tumor cells sorted ex vivo revealed that tumor cells treated with TGFβ blockade adopted a classical lineage consistent with enhanced chemosensitivity, and immunofluorescence for cleaved caspase 3 confirmed that TGFβ blockade increased chemotherapy-induced cell death in vivo. TGFβ regulates pancreatic cancer cell plasticity between classical and basal cell states. TGFβ blockade in orthotropic models of pancreatic cancer enhances sensitivity to chemotherapy by promoting a classical malignant cell state. This study provides scientific rationale for evaluation of NIS793 with FOLFIRINOX or gemcitabine/nanoparticle (albumin-bound) paclitaxel chemotherapy backbone in the clinical setting and supports the concept of manipulating cancer cell plasticity to increase the efficacy of combination therapy regimens.

中文翻译：

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胰腺癌中转化生长因子-β 阻断可增强对联合化疗的敏感性

转化生长因子-b (TGFb) 在胰腺癌中发挥多效性作用，包括促进转移、减弱 CD8 T 细胞活化、增强肌成纤维细胞分化和细胞外基质沉积。然而，单药 TGFb 抑制对小鼠或人类胰腺癌的疗效有限。我们在原位胰腺中评估了 TGFβ 阻断抗体 NIS793 与吉西他滨/纳米颗粒（白蛋白结合）紫杉醇或 FOLFIRINOX（亚叶酸 [FOL]、5-氟尿嘧啶 [F]、伊立替康 [IRI] 和奥沙利铂 [OX]）的组合癌症模型。单细胞RNA测序和免疫荧光用于评估肿瘤细胞状态和肿瘤微环境的变化。用化疗阻断 TGFβ 可减轻免疫原性较差的胰腺癌的肿瘤负荷，而不影响癌细胞的转移率。联合治疗的功效不依赖于 CD8 T 细胞，因为在 CD8 耗尽或重组激活基因 2 (RAG2) 小鼠中保留了对 TGFβ 阻断的反应。 TGFβ阻断减少了α-平滑肌肌动蛋白阳性成纤维细胞总数，但对成纤维细胞异质性影响很小。对离体分选的肿瘤细胞进行批量 RNA 测序显示，用 TGFβ 阻断处理的肿瘤细胞采用了与化疗敏感性增强一致的经典谱系，而裂解的 caspase 3 的免疫荧光证实了 TGFβ 阻断增加了化疗诱导的体内细胞死亡。 TGFβ 调节经典细胞状态和基底细胞状态之间的胰腺癌细胞可塑性。胰腺癌正交各向异性模型中的 TGFβ 阻断可通过促进经典的恶性细胞状态来增强对化疗的敏感性。这项研究为在临床环境中评估 NIS793 与 FOLFIRINOX 或吉西他滨/纳米颗粒（白蛋白结合）紫杉醇化疗骨干提供了科学依据，并支持操纵癌细胞可塑性以提高联合治疗方案疗效的概念。