Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I
Authors: Alec C Kimmelman
Suprit Gupta
Kwun Wah Wen
Seth J Parker
Douglas T Fearon
Albert S W Sohn
Keisuke Yamamoto
Anthony Venida
Joao A Paulo
Miwako Kakiuchi
Jayanta Debnath
Douglas E Biancur
Julian Yano
Grace E Kim
Joseph D Mancias
Robert S Banh
Rushika M Perera
Elaine Y Lin
Subhadip Mukhopadhyay
Journal: Nature (2020)
Discipline: Multidisciplinary
Keywords: Immune evasion; cancer treatment; antigen presentation; major histocompatibility complex class I (MHC-I); pancreatic ductal adenocarcinoma (PDAC)

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. 

Retracted: No

PubPeer comments:
 Retraction, March 2022: https: ijdvl.com retraction-histoplasmosis-affecting-oral-mucosa-in-an-immunocompetent-patient-a-rarity-in-non-disseminated-disease  The article titled u201cHistoplasmosis affecting oral mucosa in an immunocompetent patient: A rarity in non-disseminated diseaseu201d1, published on pages 214-216, issue 2, volume 88 of the Indian Journal ofDermatology, Venereology, and Leprology (IJDVL), has been retracted by the Editorial Board of the journal following an investigation. It has been noted that Figure 2 of their published article1 is the one and the same as the upper panel of Figure 3 of another article published by Sen et al2 in the Indian Journal Dermatology (IJD). Also, the Editorial Board notes the fact that neither did the authors cite the earlier published article in the article published in the current issue of our journal, nor did they offer any explanation for the same when specifically queried upon why they had not done that. The Editorial Board also notes the fact that two of the authors of the current article were the co-authors of the IJD article too, including the one who was the corresponding author of the earlier article, and both the reports were from the same department. This makes the nature of the offence particularly egregious. As the case involves the data duplication, missing citation and gross infringement of publication ethics, the Editorial Board of the IJDVL has decided to retract the article. ,