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Javitt, A.

Publications and source records attributed to Javitt, A..

2 recordsLinked to original sources
bioRxiv2021

The proteasome regulator PSME4 drives immune evasion and abrogates anti-tumor immunity in NSCLC

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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/464690v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@e87910org.highwire.dtl.DTLVardef@641843org.highwire.dtl.DTLVardef@175092corg.highwire.dtl.DTLVardef@ad34c2_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMapping the degradation landscape in Non-Small Cell Lung Cancer (NSCLC) uncovers altered proteasome activity and composition C_LIO_LIProteasome regulator PSME4 plays an anti-inflammatory role in NSCLC by attenuating immunoproteasome activity C_LIO_LIPSME4 restricts tumor antigen presentation and cytokine secretion, defining a cold tumor environment C_LIO_LIPSME4 drives tumor immune evasion and is associated with resistance to immunotherapy C_LI

cancer biology↗
bioRxiv2021

Uncovering the modified immunopeptidome reveals insights into principles of PTM-driven antigenicity

Antigen processing and presentation are critical for modulating tumor-host interactions. While post-translational modifications (PTMs) can alter the binding and recognition of antigens, their identification remains challenging. Here we uncover the role PTMs may play in antigen presentation and recognition in human cancers by profiling 29 different PTM combinations in immunopeptidomics data from multiple clinical samples and cell lines. We established and validated an antigen discovery pipeline and showed that newly identified modified antigens from a murine cancer model are cancer-specific and can elicit T cell killing. Systematic analysis of PTMs across multiple cohorts defined new haplotype preferences and binding motifs in association with specific PTM types. By expanding the antigenic landscape with modifications, we uncover disease-specific targets, including thousands of novel cancer-specific antigens and reveal insight into PTM-driven antigenicity. Collectively, our findings highlight an immunomodulatory role for modified peptides presented on HLA I, which may have broad implications for T-cell mediated therapies in cancer and beyond. SignificanceMajor efforts are underway to identify cancer-specific antigens for personalized immunotherapy. Here, we enrich the immunopeptidome landscape by uncovering thousands of novel putative antigens that are post-translationally modified. We define unique preferences for PTM-driven alterations affecting HLA binding and TCR recognition, which in turn alter tumor-immune interactions. Conflict of interest statementAuthors declare no conflicts of interest.

cancer biology↗