自噬通過降解MHC-I促進胰腺癌的免疫逃逸
作者：
小柯機器人發布時間：2020/4/30 10:35:42
近日，美國紐約大學醫學院Alec C. Kimmelman、加州大學舊金山分校Rushika M. Perera等研究人員合作發現，自噬通過降解MHC-I來促進胰腺癌的免疫逃逸。相關論文於2020年4月22日在線發表在《自然》雜誌上。
研究人員表明，在PDAC中，MHC-1分子通過涉及自噬貨物受體NBR1的自噬依賴性機制選擇性靶向溶酶體降解。PDAC細胞在細胞表面顯示MHC-1的表達降低，而在自噬體和溶酶體中表現出主要的定位。明顯地，自噬的抑制恢復了MHC-1的表面水平，並導致改善了抗原呈遞，增強了抗腫瘤T細胞反應並降低了同源宿主小鼠的腫瘤生長。
因此，通過消耗CD8+T細胞或減少MHC-1的表面表達來逆轉自噬抑制的抗腫瘤作用。通過遺傳途徑或藥理上利用氯喹來抑制自噬能夠與雙重ICB治療（抗PD1和抗CTLA4抗體）產生協同作用，並導致增強的抗腫瘤免疫應答。這些發現證明了自噬或溶酶體功能增強在免疫逃逸中的作用，即通過選擇性靶向MHC-1分子進行降解，並為自噬抑制和雙重ICB治療相結合提供了理論依據，從而可作為靶向PDAC的治療策略。
據介紹，免疫逃逸是癌症治療的主要障礙。逃避的常見機制包括由MHC-1的突變或雜合性喪失引起的抗原呈遞受損，這與免疫檢查點封鎖（ICB）治療的耐藥性有關。但是，在對包括ICB在內的大多數療法均具有抵抗力的胰腺導管腺癌（PDAC）中，儘管MHC-1的表達頻繁下調，但很少發現引起MHC-1丟失的突變。
附：英文原文
Title: Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I
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