肿瘤细胞治疗研究
英文原题：Targeting cancer-associated fibroblast autophagy renders pancreatic cancer eradicable with immunochemotherapy by inhibiting adaptive immune resistance.
越来越多的证据表明，肿瘤相关成纤维细胞（CAF）的巨自噬/自噬在肿瘤发生发展中至关重要，并可能成为胰腺导管腺癌（PDAC）的治疗靶点。
越来越多的证据表明，癌症相关成纤维细胞（CAF）的巨自噬/自噬对肿瘤发展至关重要，可能成为胰腺导管腺癌（PDAC）的治疗靶点。然而，CAF自噬在免疫监视和癌症免疫治疗中的作用尚不明确。本研究发现，抑制CAF自噬可在免疫缺陷型异种移植模型中抑制体内肿瘤发展。但在免疫功能健全的小鼠模型中，这种敲除会通过上调CD274/PD-L1水平，损害抗肿瘤免疫及体内外抗肿瘤疗效。阻断CAF自噬可减少IL-6（白细胞介素6）生成，破坏高度促纤维化的肿瘤微环境（TME），并在转录水平降低胰腺癌细胞中的USP14表达。研究进一步确认，USP14是一种翻译后调控因子，可通过去除K280位点的K63连接型泛素化而下调CD274表达。最后，采用氯喹二磷酸盐负载的间充质干细胞（MSC）脂质体精准靶向CAF并抑制其自噬，提高了免疫化疗对抗胰腺癌的疗效。缩写：AIR，适应性免疫耐受；ATRA，全反式维甲酸；CAF，癌症相关成纤维细胞；CD274/PD-L1，CD274分子；CM，条件培养基；CQ，氯喹二磷酸盐；CyTOF，质谱流式细胞术；FGF2/bFGF，成纤维细胞生长因子2；ICB，免疫检查点阻断；IF，免疫荧光；IHC，免疫组织化学；IP，免疫沉淀；MS，质谱仪；MSC，间充质干细胞；PDAC，胰腺导管腺癌；TEM，透射电子显微镜；TIL，肿瘤浸润淋巴细胞；TME，肿瘤微环境；USP14，泛素特异性肽酶14。
Accumulating evidence suggests that cancer-associated fibroblast (CAF) macroautophagy/autophagy is crucial in tumor development and may be a therapeutic target for pancreatic ductal adenocarcinoma (PDAC). However, the role of CAF autophagy during immune surveillance and cancer immunotherapy is unclear. The present study revealed that the inhibition of CAF autophagy suppresses in vivo tumor development in immune-deficient xenografts. This deletion compromises anti-tumor immunity and anti-tumor efficacy both in vitro and in vivo by upregulating CD274/PDL1 levels in an immune-competent mouse model. A block in CAF autophagy reduced the production of IL6 (interleukin 6), disrupting high desmoplastic TME and decreasing USP14 expression at the transcription level in pancreatic cancer cells. We further identify USP14 as the post-translational factor responsible for downregulating CD274 expression by removing K63 linked-ubiquitination at the K280 residue. Finally, chloroquine diphosphate-loaded mesenchymal stem cell (MSC)-liposomes, by accurately targeting CAFs, inhibited CAF autophagy, improving the efficacy of immunochemotherapy to combat pancreatic cancer. Abbreviation : AIR: adaptive immune resistance; ATRA: all-trans-retinoicacid; CAF: cancer-associated fibroblast; CD274/PDL1: CD274 molecule; CM: conditioned medium; CQ: chloroquine diphosphate; CyTOF: Mass cytometry; FGF2/bFGF: fibroblast growth factor 2; ICB: immune checkpoint blockade; IF: immunofluorescence; IHC: immunohistochemistry; IP: immunoprecipitation; MS: mass spectrometer; MSC: mesenchymal stem cell; PDAC: pancreatic ductal adenocarcinoma; TEM: transmission electron microscopy; TILs: tumor infiltrating lymphocytes; TME: tumor microenvironment; USP14: ubiquitin specific peptidase 14.
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