Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I

Abstract

Author contributions K.Y. and A.V. performed the majority of experiments and wrote the manuscript. J.Y. assisted with cloning and performed the proximity biotinylation and ubiquitylation experiments. D.E.B. and A.S.W.S. assisted with animal studies. S.G. performed immunofluorescence and analysis of patient PDAC specimens. M.K. assisted with the analysis of flow cytometry data and RNA-seq data. S.M. assisted with immunoblotting and preparing shRNAs. E.Y.L. and S.J.P. cloned fluorescent constructs. K.W.W. and G.E.K. provided PDAC patient specimens and analysis. J.D. provided GFP-NBR1 and GFP-NBR1 dUBA constructs. R.S.B. assisted with transcriptome data analysis. J.D.M. and J.A.P. performed proteomics analysis. D.T.F. provided intellectual feedback and support. R.M.P. and A.C.K. conceived the project, supervised the research, and wrote and edited the paper.Competing interests A.C.K. has financial interests in Vescor Therapeutics, LLC. A.C.K. is an inventor on patents pertaining to KRAS regulated metabolic pathways, redox control pathways in pancreatic cancer, targeting GOT1 as a therapeutic approach, and the autophagic control of iron metabolism. A.

The ORF8 Protein of SARS-CoV-2 Mediates Immune Evasion through Potently Downregulating MHC-I

“…However, the knockdown of NBR1 which participates in the MHC-I downregulation in pancreatic cancer cells did not exert any effect, excluding its involvement (Fig. S3I) 28 . Together, although we did yet not observe solid evidence for ER-phagy, at least we found that autophagy plays an important role in ORF8-mediated downregulation of MHC-I.…”

Autophagy, the innate immune response and cancer

“…MHC-I expression is elevated in DCs in the absence of Atg5 and Atg7 due to decreased endocytosis and degradation, demonstrating that autophagy can also degrade MHC-I in DCs [106]. It would be interesting to determine whether MHC-I control by autophagy in DCs is through a similar mechanism as the one described in tumour cells by Yamamoto et al (2020), involving the autophagy cargo receptor NRB1.…”

“…This was linked with an increase in scavenger receptor CD36 and increased lipid accumulation in ATG5-deficient DCs. More recently, autophagy in PDAC has been shown to selectively target MHC-I in tumour cells, causing decreased surface expression [105]. Blocking autophagy enhanced antitumour T-cell responses and had a synergistic effect with immune checkpoint blockade [105].…”

“…More recently, autophagy in PDAC has been shown to selectively target MHC-I in tumour cells, causing decreased surface expression [105]. Blocking autophagy enhanced antitumour T-cell responses and had a synergistic effect with immune checkpoint blockade [105]. MHC-I expression is elevated in DCs in the absence of Atg5 and Atg7 due to decreased endocytosis and degradation, demonstrating that autophagy can also degrade MHC-I in DCs [106].…”

Cell Death in the Tumor Microenvironment: Implications for Cancer Immunotherapy

“…Within the center or core of the tumor, poor vascularization prevents oxygen and glucose from reaching these cells leading to hypoxia and depletion of ATP. Recent studies also show that in pancreatic ductal adenocarcinoma (PDAC) MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1 [ 126 ]. Therefore, hypoxic autophagy could have an unanticipated consequence to drive immune escape in the tumor microenvironment.…”