Oyama Koki, Nakata Kohei, Tsutsumi Chikanori, Hayashi Masataka, Zhang Bo, Mochida Yuki, Shinkawa Tomohiko, Hirotaka Kento, Zhong Pingshan, Date Satomi, Luo Haizhen, Kubo Akihiro, Higashijima Nobuhiro, Yamada Yutaka, Abe Toshiya, Ideno Noboru, Koikawa Kazuhiro, Iwamoto Chika, Ikenaga Naoki, Ohuchida Kenoki, Onishi Hideya, Morisaki Takashi, Kuba Keiji, Oda Yoshinao, Nakamura Masafumi
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Endoscopic Diagnostics and Therapeutics, Kyushu University Hospital, Fukuoka, Japan.
Cancer Res. 2024 Dec 16;84(24):4214-4232. doi: 10.1158/0008-5472.CAN-24-0830.
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.
由于肿瘤免疫微环境的抑制作用，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。自噬已被证明在抗肿瘤免疫中发挥作用，有人提出将其作为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，癌细胞中的自噬抑制可诱导树突状细胞（DC）激活。对人类PDAC肿瘤的分析证实了自噬与DC激活特征之间呈负相关。从机制上讲，自噬抑制增加了肿瘤抗原的细胞内积累，从而激活DC。给予自噬抑制剂氯喹与Flt3配体诱导的DC浸润相结合可抑制肿瘤生长并增加肿瘤浸润性T淋巴细胞。然而，癌细胞中的自噬抑制也会诱导免疫检查点LAG3高表达的CD8+T细胞耗竭。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小鼠模型中显著降低了肿瘤生长。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，有必要进一步开发这种治疗方法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激活，并与免疫疗法协同作用，显著抑制胰腺导管腺癌的生长。
