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Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation

ABSTRACT: One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine thatpotetiate T cell-mediated cytotoxicity, we identified atractylenolide I (ATT-I) that significantly promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of CD8+ T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non-ATPase 4 (PSMD4), an essential component of the immunoproteasome complex,as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigenprocessing activity of immunoproteasome, leading to enhanced major histocompatibility class I(MHC-I)-mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient-derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of CD8+ T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation, empowers T-cell cytotoxicity, and thus elevates the tumorresponse to immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE171158 | GEO | 2021/03/31

REPOSITORIES: GEO

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Project description:Cerebral malaria (CM) lethality is attributable to brain edema induction but the cellular mechanisms involving brain microvascular endothelium in CM pathogenesis are unexplored. Activation of the STING-INFb-CXCL10 axis in brain endothelial cells (BECs) is a prominent component of the innate immune response in cerebral malaria (CM) development in mouse models. Using a T cell-reporter system, we show that Type 1 IFN signaling in BECs exposed to Plasmodium berghei-infected erythrocytes (PbA-IE), functionally enhances MHC Class-I antigen presentation through gamma-interferon independent immunoproteasome activation and impacted the proteome functionally related to vesicle trafficking, protein processing, and folding and antigen presentation. In vitro assays show that Type 1 IFN signaling and immunoproteasome activation are also involved in the dysfunction of the endothelial barrier through disturbing gene expression in the Wnt/ß-catenin signaling pathway. We demonstrate that IE exposure induces a substantial increase in BECs glucose uptake while glycolysis blockade abrogates INFb secretion impairing immunoproteasome activation, antigen presentation, and Wnt/ ß-catenin signaling. Metabolome analysis show that energy demand and production are markedly increased in BECs exposed to IE as revealed by enriched content in glucose and fatty acid catabolites. In accordance, glycolysis blockade in vivo delayed the clinical onset of CM in mice. Our results unveiled that Type 1 IFN signaling and subsequent immunoproteasome activation in BECs contribute to enhanced antigen presentation and the impairment of the endothelial barrier function. We also show that Type 1 IFN signaling and its downstream effects are licensed by dramatic increase in glucose uptake with an impact on energy metabolism pathways. This work raises the hypothesis that Type 1 IFN- immunoproteasome induction response in BECs contributes to CM pathology and fatality (1) by increasing antigen presentation to cytotoxic CD8+ T cells, which is a determinant of brain cytotoxic edema and (2) by promoting endothelial barrier dysfunction, that likely favors brain vasogenic edema.

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Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation

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