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Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I

Author

Listed:
  • Keisuke Yamamoto

    (New York University School of Medicine)

  • Anthony Venida

    (University of California, San Francisco)

  • Julian Yano

    (University of California, San Francisco)

  • Douglas E. Biancur

    (New York University School of Medicine)

  • Miwako Kakiuchi

    (Columbia University College of Physicians and Surgeons
    Columbia University College of Physicians and Surgeons)

  • Suprit Gupta

    (University of California, San Francisco)

  • Albert S. W. Sohn

    (New York University School of Medicine)

  • Subhadip Mukhopadhyay

    (New York University School of Medicine)

  • Elaine Y. Lin

    (New York University School of Medicine)

  • Seth J. Parker

    (New York University School of Medicine)

  • Robert S. Banh

    (New York University School of Medicine)

  • Joao A. Paulo

    (Harvard Medical School)

  • Kwun Wah Wen

    (University of California, San Francisco)

  • Jayanta Debnath

    (University of California, San Francisco
    University of California, San Francisco)

  • Grace E. Kim

    (University of California, San Francisco)

  • Joseph D. Mancias

    (Dana-Farber Cancer Institute, Harvard Medical School)

  • Douglas T. Fearon

    (Cold Spring Harbor Laboratory
    Weill Cornell Medicine
    University of Cambridge, Robinson Way)

  • Rushika M. Perera

    (University of California, San Francisco
    University of California, San Francisco
    University of California, San Francisco)

  • Alec C. Kimmelman

    (New York University School of Medicine)

Abstract

Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy1–3. However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found5 despite the frequent downregulation of MHC-I expression6–8. Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8+ T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.

Suggested Citation

  • Keisuke Yamamoto & Anthony Venida & Julian Yano & Douglas E. Biancur & Miwako Kakiuchi & Suprit Gupta & Albert S. W. Sohn & Subhadip Mukhopadhyay & Elaine Y. Lin & Seth J. Parker & Robert S. Banh & Jo, 2020. "Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I," Nature, Nature, vol. 581(7806), pages 100-105, May.
  • Handle: RePEc:nat:nature:v:581:y:2020:i:7806:d:10.1038_s41586-020-2229-5
    DOI: 10.1038/s41586-020-2229-5
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    Cited by:

    1. Zi-Yi Han & Zhuang-Jiong Fu & Yu-Zhang Wang & Cheng Zhang & Qi-Wen Chen & Jia-Xin An & Xian-Zheng Zhang, 2024. "Probiotics functionalized with a gallium-polyphenol network modulate the intratumor microbiota and promote anti-tumor immune responses in pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Lucia Taraborrelli & Yasin Şenbabaoğlu & Lifen Wang & Junghyun Lim & Kerrigan Blake & Noelyn Kljavin & Sarah Gierke & Alexis Scherl & James Ziai & Erin McNamara & Mark Owyong & Shilpa Rao & Aslihan Ka, 2023. "Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Z. L. Liu & X. Y. Meng & R. J. Bao & M. Y. Shen & J. J. Sun & W. D. Chen & F. Liu & Y. He, 2024. "Single cell deciphering of progression trajectories of the tumor ecosystem in head and neck cancer," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    4. Nina Frey & Luigi Tortola & David Egli & Sharan Janjuha & Tanja Rothgangl & Kim Fabiano Marquart & Franziska Ampenberger & Manfred Kopf & Gerald Schwank, 2022. "Loss of Rnf31 and Vps4b sensitizes pancreatic cancer to T cell-mediated killing," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    5. Zhen Lu & Jinyun Chen & Pengfei Yu & Matthew J. Atherton & Jun Gui & Vivek S. Tomar & Justin D. Middleton & Neil T. Sullivan & Sunil Singhal & Subin S. George & Ashley G. Woolfork & Aalim M. Weljie & , 2022. "Tumor factors stimulate lysosomal degradation of tumor antigens and undermine their cross-presentation in lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    6. Yalan Deng & Xianghou Xia & Yang Zhao & Zilong Zhao & Consuelo Martinez & Wenjuan Yin & Jun Yao & Qinglei Hang & Weiche Wu & Jie Zhang & Yang Yu & Weiya Xia & Fan Yao & Di Zhao & Yutong Sun & Haoqiang, 2021. "Glucocorticoid receptor regulates PD-L1 and MHC-I in pancreatic cancer cells to promote immune evasion and immunotherapy resistance," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    7. Bo Jiang & Xiaozhi Zhao & Wei Chen & Wenli Diao & Meng Ding & Haixiang Qin & Binghua Li & Wenmin Cao & Wei Chen & Yao Fu & Kuiqiang He & Jie Gao & Mengxia Chen & Tingsheng Lin & Yongming Deng & Chao Y, 2022. "Lysosomal protein transmembrane 5 promotes lung-specific metastasis by regulating BMPR1A lysosomal degradation," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    8. Wanzun Lin & Li Chen & Haojiong Zhang & Xianxin Qiu & Qingting Huang & Fangzhu Wan & Ziyu Le & Shikai Geng & Anlan Zhang & Sufang Qiu & Long Chen & Lin Kong & Jiade J. Lu, 2023. "Tumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    9. Xiaoyu Liu & Yaping Zhuang & Wei Huang & Zhuozhuo Wu & Yingjie Chen & Qungang Shan & Yuefang Zhang & Zhiyuan Wu & Xiaoyi Ding & Zilong Qiu & Wenguo Cui & Zhongmin Wang, 2023. "Interventional hydrogel microsphere vaccine as an immune amplifier for activated antitumour immunity after ablation therapy," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    10. Lianmei Tan & Tao Yin & Handan Xiang & Liuyang Wang & Poorva Mudgal & Junying Chen & Yi Ding & Guoping Wang & Bryan Jian Wei Lim & Yuqi Huang & De Huang & Yaosi Liang & Peter B. Alexander & Kun Xiang , 2024. "Aberrant cytoplasmic expression of UHRF1 restrains the MHC-I-mediated anti-tumor immune response," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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