Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I
Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I
复制标题
自噬通过降解MHC-I促进胰腺癌的免疫逃避
DOI：
10.1038/s41586-020-2229-5
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发表时间：
2020-04-22
期刊：
影响因子：
64.8
通讯作者：
Kimmelman, Alec C.
中科院分区：
文献类型：
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作者：
Yamamoto, Keisuke;Venida, Anthony;Kimmelman, Alec C.
免疫逃避是癌症治疗的主要障碍。常见的逃避机制包括主要组织相容性复合体I类(MHC-I)的突变或杂合性丢失导致的抗原提呈受损，这与免疫检查点阻断(ICB)治疗的抵抗有关(1-3)。然而，在对包括ICB4在内的大多数治疗方案耐药的胰腺导管腺癌(PDAC)中，尽管MHC-I表达频繁下调(6-8)，但很少发现导致MHC-I基因缺失的突变(5)。在这里，我们表明，在PDAC中，MHC-I分子通过涉及自噬货物受体NBR1的自噬依赖机制选择性地针对溶酶体降解。PDAC细胞表面MHC-I表达减少，主要定位于自噬小体和溶酶体。值得注意的是，抑制自噬可以恢复MHC-I的表面水平，并导致改善抗原提呈，增强抗肿瘤T细胞反应，并减少同基因宿主小鼠的肿瘤生长。因此，通过耗尽CD8(+)T细胞或减少MHC-I的表面表达，自噬抑制的抗肿瘤作用被逆转。用氯喹从基因或药理上抑制自噬，与双重ICB疗法(抗PD1和抗CTLA4抗体)协同作用，并导致增强的抗肿瘤免疫反应。我们的研究结果表明，通过选择性靶向MHC-I分子进行降解，增强自噬或溶酶体功能在免疫逃避中的作用，并为自噬抑制和双重ICB治疗相结合作为抗PDAC的治疗策略提供了理论基础。抑制自噬-溶酶体系统上调MHC-I类蛋白的表面表达，增强抗原呈递，并激发由CD8(+)T细胞介导的强大的抗肿瘤免疫反应。
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.