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Combined Autophagy Inhibition and Dendritic Cell Recruitment Induces Antitumor Immunity and Enhances Immune Checkpoint Blockade Sensitivity in Pancreatic Cancer
Cancer Research ( IF 12.5 ) Pub Date : 2024-09-17 , DOI: 10.1158/0008-5472.can-24-0830 Koki Oyama 1 , Kohei Nakata 2 , Chikanori Tsutsumi 3 , Masataka Hayashi 2 , Bo Zhang 2 , Yuki Mochida 3 , Tomohiko Shinkawa 2 , Kento Hirotaka 1 , Pingshan Zhong 2 , Satomi Date 2 , Haizhen Luo 2 , Akihiro Kubo 2 , Nobuhiro Higashijima 2 , Yutaka Yamada 4 , Toshiya Abe 5 , Noboru Ideno 2 , Kazuhiro Koikawa 2 , Chika Iwamoto 3 , Naoki Ikenaga 3 , Kenoki Ohuchida 2 , Hideya Onishi 6 , Takashi Morisaki 7 , Keiji Kuba 2 , Yoshinao Oda 3 , Masafumi Nakamura 3
Cancer Research ( IF 12.5 ) Pub Date : 2024-09-17 , DOI: 10.1158/0008-5472.can-24-0830 Koki Oyama 1 , Kohei Nakata 2 , Chikanori Tsutsumi 3 , Masataka Hayashi 2 , Bo Zhang 2 , Yuki Mochida 3 , Tomohiko Shinkawa 2 , Kento Hirotaka 1 , Pingshan Zhong 2 , Satomi Date 2 , Haizhen Luo 2 , Akihiro Kubo 2 , Nobuhiro Higashijima 2 , Yutaka Yamada 4 , Toshiya Abe 5 , Noboru Ideno 2 , Kazuhiro Koikawa 2 , Chika Iwamoto 3 , Naoki Ikenaga 3 , Kenoki Ohuchida 2 , Hideya Onishi 6 , Takashi Morisaki 7 , Keiji Kuba 2 , Yoshinao Oda 3 , Masafumi Nakamura 3
Affiliation
The effect of immune checkpoint inhibitors is extremely limited in patients with pancreatic ductal adenocarcinoma (PDAC) due to the suppressive tumor immune microenvironment (TIME). Autophagy, which has been shown to play a role in anti-tumor immunity, has been proposed as a therapeutic target for PDAC. Here, 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 intracellular accumulation of tumor antigens, which could activate DCs. Administration of chloroquine (CQ), an autophagy inhibitor, in combination with Flt3 ligand (Flt3L)-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 CQ, Flt3L, and an anti-LAG3 antibody markedly reduced tumor growth in orthotopic syngeneic PDAC mouse models. Thus, targeting autophagy in cancer cells and activating DCs sensitizes PDAC tumors to immune checkpoint inhibitor therapy, warranting further development of this treatment approach to overcome immunosuppression in pancreatic cancer.
中文翻译:
自噬抑制和树突状细胞募集相结合可诱导抗肿瘤免疫并增强胰腺癌中免疫检查点封锁的敏感性
由于抑制性肿瘤免疫微环境(TIME),免疫检查点抑制剂对胰腺导管腺癌(PDAC)患者的作用极其有限。自噬已被证明在抗肿瘤免疫中发挥作用,已被提议作为 PDAC 的治疗靶点。在这里,自噬缺陷型小鼠 PDAC 肿瘤的单细胞 RNA 测序表明,癌细胞中的自噬抑制诱导树突状细胞 (DC) 激活。对人类 PDAC 肿瘤的分析证实了自噬和 DC 激活特征之间的负相关性。从机制上讲,自噬抑制会增加肿瘤抗原的细胞内积累,从而激活树突状细胞。给予自噬抑制剂氯喹 (CQ) 与 Flt3 配体 (Flt3L) 联合诱导的 DC 浸润可抑制肿瘤生长并增加肿瘤浸润 T 淋巴细胞。然而,癌细胞中的自噬抑制也会导致 CD8+ T 细胞耗竭,并导致免疫检查点 LAG3 高表达。包含 CQ、Flt3L 和抗 LAG3 抗体的三联疗法显着减少了原位同基因 PDAC 小鼠模型中的肿瘤生长。因此,靶向癌细胞中的自噬并激活 DC 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。
更新日期:2024-09-17
中文翻译:
自噬抑制和树突状细胞募集相结合可诱导抗肿瘤免疫并增强胰腺癌中免疫检查点封锁的敏感性
由于抑制性肿瘤免疫微环境(TIME),免疫检查点抑制剂对胰腺导管腺癌(PDAC)患者的作用极其有限。自噬已被证明在抗肿瘤免疫中发挥作用,已被提议作为 PDAC 的治疗靶点。在这里,自噬缺陷型小鼠 PDAC 肿瘤的单细胞 RNA 测序表明,癌细胞中的自噬抑制诱导树突状细胞 (DC) 激活。对人类 PDAC 肿瘤的分析证实了自噬和 DC 激活特征之间的负相关性。从机制上讲,自噬抑制会增加肿瘤抗原的细胞内积累,从而激活树突状细胞。给予自噬抑制剂氯喹 (CQ) 与 Flt3 配体 (Flt3L) 联合诱导的 DC 浸润可抑制肿瘤生长并增加肿瘤浸润 T 淋巴细胞。然而,癌细胞中的自噬抑制也会导致 CD8+ T 细胞耗竭,并导致免疫检查点 LAG3 高表达。包含 CQ、Flt3L 和抗 LAG3 抗体的三联疗法显着减少了原位同基因 PDAC 小鼠模型中的肿瘤生长。因此,靶向癌细胞中的自噬并激活 DC 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。