小柯机器人

近日，美国纽约大学医学院Alec C. Kimmelman、加州大学旧金山分校Rushika M. Perera等研究人员合作发现，自噬通过降解MHC-I来促进胰腺癌的免疫逃逸。相关论文于2020年4月22日在线发表在《自然》杂志上。

研究人员表明，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MHC-1的表达降低，而在自噬体和溶酶体中表现出主要的定位。明显地，自噬的抑制恢复了MHC-1的表面水平，并导致改善了抗原呈递，增强了抗肿瘤T细胞反应并降低了同源宿主小鼠的肿瘤生长。

因此，通过消耗CD8+T细胞或减少MHC-1的表面表达来逆转自噬抑制的抗肿瘤作用。通过遗传途径或药理上利用氯喹来抑制自噬能够与双重ICB治疗（抗PD1和抗CTLA4抗体）产生协同作用，并导致增强的抗肿瘤免疫应答。这些发现证明了自噬或溶酶体功能增强在免疫逃逸中的作用，即通过选择性靶向MHC-1分子进行降解，并为自噬抑制和双重ICB治疗相结合提供了理论依据，从而可作为靶向PDAC的治疗策略。

据介绍，免疫逃逸是癌症治疗的主要障碍。逃避的常见机制包括由MHC-1的突变或杂合性丧失引起的抗原呈递受损，这与免疫检查点封锁（ICB）治疗的耐药性有关。但是，在对包括ICB在内的大多数疗法均具有抵抗力的胰腺导管腺癌（PDAC）中，尽管MHC-1的表达频繁下调，但很少发现引起MHC-1丢失的突变。

附：英文原文

Author: 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, Joao A. Paulo, Kwun Wah Wen, Jayanta Debnath, Grace E. Kim, Joseph D. Mancias, Douglas T. Fearon, Rushika M. Perera, Alec C. Kimmelman

Issue&Volume: 2020-04-22

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) therapy1,2,3. 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 expression6,7,8. 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.

DOI: 10.1038/s41586-020-2229-5

Source: https://www.nature.com/articles/s41586-020-2229-5

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