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首页> 外文期刊>Nature >Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-Ⅰ
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Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-Ⅰ

机译：自噬通过降解MHC-Ⅰ促进胰腺癌的免疫逃逸

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摘要

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) therapy(1-3). However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found(5) despite the frequent downregulation of MHC-I expression(6-8). 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.Inhibition of the autophagy-lysosome system upregulates surface expression of MHC class I proteins and enhances antigen presentation, and evokes a potent anti-tumour immune response that is mediated by CD8(+) T cells.
机译：免疫逃避是癌症治疗的主要障碍。逃逸的常见机制包括由主要组织相容性复合物I类（MHC-1）的突变或杂合性丧失引起的抗原呈递受损，这与免疫检查点阻断（ICB）治疗的耐药性有关（1-3）。然而，在对包括ICB4在内的大多数疗法有抵抗力的胰腺导管腺癌（PDAC）中，尽管MHC-1表达频繁下调（6-8），但很少发现引起MHC-1丢失的突变（5）。在这里，我们表明，在PDAC中，MHC-1分子通过涉及自噬货物受体NBR1的自噬依赖性机制选择性靶向溶酶体降解。 PDAC细胞在细胞表面显示出降低的MHC-1表达，而是在自噬体和溶酶体中表现出主要的定位。值得注意的是，自噬的抑制恢复了MHC-1的表面水平，并导致了同源宿主小鼠中抗原呈递的改善，抗肿瘤T细胞应答的增强和肿瘤生长的降低。因此，自噬抑制的抗肿瘤作用通过消耗CD8（+）T细胞或减少MHC-1的表面表达而得以逆转。在基因或药理学上抑制自噬与氯喹的协同作用与双重ICB治疗（抗PD1和抗CTLA4抗体）协同作用，并导致增强的抗肿瘤免疫应答。我们的发现证明了通过选择性靶向MHC-1分子降解来增强自噬或溶酶体功能在免疫逃逸中的作用，并为自噬抑制和双重ICB疗法相结合提供了理论依据，作为针对PDAC的治疗策略。 -溶酶体系统上调MHC I类蛋白的表面表达并增强抗原呈递，并引起CD8（+）T细胞介导的有效抗肿瘤免疫应答。

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    《Nature》 |2020年第7806期|100-105|共6页
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    NYU Sch Med Perlmutter Canc Ctr Dept Radiat Oncol New York NY 10003 USA;

    Univ Calif San Francisco Dept Anat San Francisco CA 94143 USA;

    Columbia Univ Coll Phys & Surg Columbia Ctr Translat Immunol 630 W 168th St New York NY 10032 USA|Columbia Univ Coll Phys & Surg Columbia Stem Cell Initiat 630 W 168th St New York NY 10032 USA;

    Harvard Med Sch Dept Cell Biol Boston MA 02115 USA;

    Univ Calif San Francisco Dept Pathol San Francisco CA 94140 USA;

    Univ Calif San Francisco Dept Pathol San Francisco CA 94140 USA|Univ Calif San Francisco Helen Diller Family Comprehens Canc Ctr San Francisco CA 94143 USA;

    Harvard Med Sch Dana Farber Canc Inst Dept Radiat Oncol Div Radiat & Genome Stabil Boston MA 02115 USA;

    Cold Spring Harbor Lab POB 100 Cold Spring Harbor NY 11724 USA|Weill Cornell Med New York NY USA|Univ Cambridge Canc Res UK Cambridge Inst Robinson Way Cambridge England;

    Univ Calif San Francisco Dept Anat San Francisco CA 94143 USA|Univ Calif San Francisco Dept Pathol San Francisco CA 94140 USA|Univ Calif San Francisco Helen Diller Family Comprehens Canc Ctr San Francisco CA 94143 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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