肿瘤细胞治疗研究
英文原题：The TGF-βR1 inhibitor galunisertib re-shapes the PDAC-TME by limiting decidual-like natural killer cells polarization.
胰腺导管腺癌（PDAC）是全球癌症相关死亡的第三大原因。
胰腺导管腺癌（PDAC）是全球癌症相关死亡的第三大原因。自然杀伤（NK）细胞对肿瘤监视至关重要，但在PDAC中功能失调。我们评估了在PDAC细胞和癌症相关成纤维细胞（CAFs）中药理学阻断TGF-β1/TGF-βR1轴是否可通过可溶性因子调节NK极化。比较了PDAC患者与健康对照（HC）NK细胞的表型/功能，并通过流式细胞术评估了暴露于PDAC细胞和成纤维细胞条件培养基的NK细胞的极化状态。评估了galunisertib（GAL）在免疫活性小鼠原位植入FC1199 PDAC细胞后逆转NK功能障碍的能力。PDAC患者显示TGF-β1/TGF-βR1水平高于HC，TGF-β1高/TGF-βR1高患者预后更差。与HC相比，PDAC患者循环CD9+ NK细胞扩增，与CD9- NK细胞相比，其表现出促血管生成分泌组以及更高的体外和体内（水蛭Hirudo verbana）促血管生成活性。PDAC细胞和CAF诱导CD9+蜕膜样表型，同时损害NK脱颗粒。GAL治疗抑制PDAC细胞/CAF诱导的NK无能，恢复其细胞毒性。此外，PDAC细胞中TGFβ-R1敲低表现出限制蜕膜样NK生成的能力，同时通过可溶性因子恢复其抗肿瘤能力。BxPC3和MIAPaCA2 PDAC细胞系及CAFs的分泌组分析显示，GAL下调了多种生长、血管生成和免疫调节因子的释放，包括FGF2、HGF、IL11、PLGF、EGFR和VEGF。在FC1199细胞形成的原位肿瘤体内，GAL降低了CD9+NK频率，促进M1-巨噬细胞极化，并激活NK和CD8+T细胞，同时显著降低肿瘤重量、纤维化并抑制血管生成。我们的研究将CD9+NKs鉴定为PDAC中扩增的一种新型细胞亚群，并强调了TGF-β1/TGF-βR1信号在促进促肿瘤NKs中的作用。GAL治疗作为一种免疫调节剂出现，能够在PDAC中重新教育促肿瘤NKs细胞。
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality worldwide. Natural Killer (NKs) cells are pivotal for tumor surveillance but are dysfunctional in PDAC. We evaluated whether pharmacological blockade of TGF-β1/TGF-βR1 axis in PDAC cells and cancer-associated fibroblasts (CAFs) could modulate NK polarization via soluble factors. The phenotype/functions of NKs from PDAC patients versus healthy controls (HC) were compared, and the polarization state of NKs exposed to the conditioned media of PDAC cells and fibroblasts was evaluated by flow cytometry. The ability of galunisertib (GAL) to reverse NK dysfunction in immunocompetent mice orthotopically implanted with FC1199 PDAC cells was evaluated. PDAC patients showed higher TGF-β1/ TGF-βR1 levels than HC, with worse outcomes in TGF-β1 high /TGF-βR1 high patients. Circulating CD9 + NKs were expanded in PDAC patients compared with HC and exhibited a pro-angiogenic secretome and higher pro-angiogenic activities in vitro and in vivo (leech Hirudo verbana), compared to the CD9 - NK cells. PDAC cells and CAF induced a CD9 + -decidual-like phenotype, also impairing NK degranulation. GAL treatment restrains PDAC cell/CAF-induced NK anergy, restoring their cytotoxicity. Also, TGFβ-R1 knockdown in PDAC cells exhibited the capability to limit the generation of decidual-like NKs, while restoring their antitumor ability, via soluble factors. Secretome profiling of BxPC3 and MIAPaCA2 PDAC cell lines and CAFs showed that GAL downregulated the release of several growth, angiogenic, and immunoregulatory factors, including FGF2, HGF, IL11, PLGF, EGFR, and VEGF. In vivo in orthotopic tumors formed by FC1199 cells GAL decreased CD9 + -NK frequency, promoted M1-macrophage polarization, and activated NK and CD8 + T-cells, together with a significant reduction of tumor weight, fibrosis and inhibition of angiogenesis. Our study identifies CD9 + NKs as a novel cell subset expanded in PDAC and underscores the role of TGF-β1/TGF-βR1 signalling in promoting a pro-tumoral NKs. GAL-treatment emerges as immunomodulator able in re-educating pro-tumor NKs cells in PDAC.
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