肿瘤细胞治疗研究
英文原题：Combined Autophagy Inhibition and Dendritic Cell Recruitment Induces Antitumor Immunity and Enhances Immune Checkpoint Blockade Sensitivity in Pancreatic Cancer.
Combined Autophagy Inhibition and Dendritic Cell Recruitment Induces Antitumor Immunity and Enhances Immune Checkpoint Blockade Sensitivity in Pancreatic Cancer.
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免疫检查点抑制剂在胰腺导管腺癌（PDAC）患者中的疗效极为有限，原因在于抑制性肿瘤免疫微环境。自噬已被证明在抗肿瘤免疫中发挥作用，并被提出作为PDAC的治疗靶点。在本研究中，对自噬缺陷型小鼠PDAC肿瘤进行单细胞RNA测序发现，癌细胞中自噬抑制诱导了树突状细胞（DC）活化。对人类PDAC肿瘤的分析证实了自噬与DC活化特征之间存在负相关。在机制上，自噬抑制增加了肿瘤抗原的细胞内积累，从而能够激活DC。给予自噬抑制剂氯喹，联合Flt3配体诱导的DC浸润，抑制了肿瘤生长并增加了肿瘤浸润T淋巴细胞。然而，癌细胞中的自噬抑制也诱导了CD8+ T细胞耗竭，伴有免疫检查点LAG3的高表达。由氯喹、Flt3配体和抗LAG3抗体组成的三联疗法在原位同基因PDAC小鼠模型中显著减少了肿瘤生长。因此，靶向癌细胞中的自噬并激活DC可使PDAC肿瘤对免疫检查点抑制剂治疗敏感，值得进一步开发这一治疗策略以克服胰腺癌中的免疫抑制。意义：抑制胰腺癌细胞中的自噬可增强肿瘤抗原的细胞内积累，从而诱导树突状细胞活化，并与免疫治疗协同显著抑制胰腺导管腺癌的生长。
The effect of immune checkpoint inhibitors is extremely limited in patients with pancreatic ductal adenocarcinoma (PDAC) due to the suppressive tumor immune microenvironment. Autophagy, which has been shown to play a role in antitumor immunity, has been proposed as a therapeutic target for PDAC.
In this study, single-cell RNA sequencing of autophagy-deficient murine PDAC tumors revealed that autophagy inhibition in cancer cells induced dendritic cell (DC) activation. Analysis of human PDAC tumors substantiated a negative correlation between autophagy and DC activation signatures.
Mechanistically, autophagy inhibition increased the intracellular accumulation of tumor antigens, which could activate DCs. Administration of chloroquine, an autophagy inhibitor, in combination with Flt3 ligand-induced DC infiltration inhibited tumor growth and increased tumor-infiltrating T lymphocytes.
However, autophagy inhibition in cancer cells also induced CD8+ T-cell exhaustion with high expression of immune checkpoint LAG3. A triple-therapy comprising chloroquine, Flt3 ligand, and an anti-LAG3 antibody markedly reduced tumor growth in orthotopic syngeneic PDAC mouse models.
Thus, targeting autophagy in cancer cells and activating DCs sensitize PDAC tumors to immune checkpoint inhibitor therapy, warranting further development of this treatment approach to overcome immunosuppression in pancreatic cancer. Significance: Inhibiting autophagy in pancreatic cancer cells enhances intracellular accumulation of tumor antigens to induce dendritic cell activation and synergizes with immunotherapy to markedly inhibit the growth of pancreatic ductal adenocarcinoma.
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