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Preprint (Author's original)CC BY-NC-ND V4.0, Open Access
Journal article
The proteasome regulator PSME4 drives immune evasion and abrogates anti-tumor immunity in NSCLC
Nature cancer
24/Oct/2021
Abstract
Protein degradation by proteasomes is important for the immune response against tumors. Antigens generated by the proteasome promote immune cell infiltration into tumors and improve tumors’ responses to immunotherapy. For example, immunoproteasomes – a subset of proteasomes induced by inflammatory signals – may improve the response of melanomas to immune checkpoint inhibitors (ICI) by eliciting tumor inflammation. Yet, it is unclear whether and how protein degradation by proteasomes impacts cancer progression and contributes to immune evasion and resistance. Here, we profile the proteasome-cleaved peptides in lung cancers and find that PSME4 serves as a novel inhibitory regulator of the immunoproteasome, playing an anti-inflammatory role in cancer. Biochemical assays combined with scRNA-seq, immunopeptidomics and in vivo analyses demonstrate that PSME4 promotes an immunosuppressive environment around the tumor and abrogates anti-tumor immunity by inhibiting antigen presentation and attenuating tumor inflammation. Furthermore, we find that PSME4 expression is correlated with responsiveness to ICI across several cancer types. Our findings suggest that PSME4-mediated regulation of proteasome activity is a novel mechanism of immune evasion in non-small-cell lung carcinoma and may be targeted therapeutically for restoring anti-tumor immunity.
Details
- Title
- The proteasome regulator PSME4 drives immune evasion and abrogates anti-tumor immunity in NSCLC
- Creators
- Aaron Javitt - 972WIS_INST___121Merav Shmueli - 972WIS_INST___121Matthias Kramer - 972WIS_INST___121Aleksandra Kolodziejczyk - 972WIS_INST___121Ivan Cohen - 972WIS_INST___121Iris Kamer - Sheba Medical CenterKevin Litchfield - The Francis Crick InstituteElizabeta Bab-Dinitz - Tel Aviv UniversityOranit Zadok - Sheba Medical CenterVanessa Neiens - Ludwig Maximilian University of MunichAdi Ulman - 972WIS_INST___121Lihi Radomir - 972WIS_INST___121Hila Wolf-Levy - Weizmann Institute of ScienceAvital Eisenberg-LernerAssaf Kacen - 972WIS_INST___121Michal AlonAna Toste Rêgo - MRC Laboratory of Molecular BiologyElvira Stacher-Priehse - Asklepios Fachkliniken München-GautingMichael Lindner - Asklepios Fachkliniken München-GautingIna Koch - Asklepios Fachkliniken München-GautingJair Bar - Sheba Medical CenterCharles Swanton - The Francis Crick InstituteYardena Samuels - 972WIS_INST___122Yishai Levin - 972WIS_INST___890Paula C. A. da Fonseca - University of GlasgowEran Elinav - 972WIS_INST___121Nir FriedmanSilke Meiners - Helmholtz Zentrum MünchenYifat Merbl (Corresponding Author) - 972WIS_INST___121
- Resource Type
- Journal article
- Publication Details
- Nature cancer
- Grant note
- We thank the members of the Merbl lab as well as Ayelet Erez and Bareket Dassa for discussion and critical reading of the manuscript. We would like to thank Alfred Zippelius for KP1.9 cells. Y.M. is supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 677748); The I-CORE Program of the Planning and Budgeting Committee and The Israel Science Foundation (Grant No. 1775/12) and the Israeli Science Foundation (Grant No. 2109/18); The Gruber Peter & Patricia award. M.D.S. is supported by Marie Sklodowska-Curie Individual Fellowship (Horizon 2020 Grant No. GAP-845066). Y.M. the incumbent of the Leonard and Carol Berall Career Development Chair generously supported by Dr. Celia and Dr. Lutz Zwillenberg-Fridman and Miel de Botton. This manuscript was edited at Life Science Editors. Author Contributions: AJ, MDS and YM conceived, designed and interpreted experiments and wrote the manuscript. AE-L and SM provided feedback on the manuscript. MDS, AU, HW-L, AE-L proteomics preparation and MDS for in vitro work. MPK,IC and LR in vivo and immunofluorescence. AAK, MPK and AJ performed and analyzed the scRNAseq experiment. MDS and DS performed the bulk RNAseq. AJ and KL analyzed the ICI cohort. IK, EBD and OZ conducted the immunohistochemistry. VN, ESP, ML, and IK analysis of German patient cohort. AK managed NSCLC Israeli cohort. MA and MDS performed immunopeptidomics and AJ analyzed. YL Mass spectrometry. ATR and PDF purified recombinant PSME4. MDS performed all other cellular and biochemical assays. AJ performed all other bioinformatics. JB, YS,EE, NF, CS SM, and YM funded and supervised the work of respective group members and YM supervised the study. AJ and MDS contributed equally to the manuscript and therefore it should be cited as Javitt A. and Shmueli M.D. et al. or Shmueli M.D. and Javitt A. et al.
- Record Identifier
- 993440884603596
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