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UBE2D3 is an Intracellular Checkpoint in Pancreatic Ductal Carcinoma that Restricts CD8+ T-Cell Antitumor Immunity

ABSTRACT: Ubiquitylation is pivotal in regulating cellular responses, with its aberration implicated in tumor immune evasion. However, the impact of ubiquitin-conjugating enzymes (E2s) on this evasion remains unclear. Here, we employ a systematic approach to demonstrate that in pancreatic ductal carcinoma (PDAC), the inflammatory microenvironment induces overexpression of the E2 enzyme UBE2D3, contributing to tumor progression through non-oncogene codependent disorders. Through gene expression analyses and functional investigations, we elucidate a mechanism wherein cancer cells evade T cell immune responses by UBE2D3 binding to the ubiquitin ligase KLHL13 to co-ubiquitinate TAP2. This K63-linkage ubiquitination at the lysine 245 site of TAP2 impedes antigenic peptide transport by the TAP1/TAP2 complex, hindering p-MHC assembly and presentation in cancer cells. We demonstrate that genetic inhibition of UBE2D3 enhances tumor-specific CD8+ T cell proliferation and extends effector-memory-like phenotypes. Building on this, we develop a small-molecule inhibitor, QX-6, targeting the active site of UBE2D3 to disrupt its function. Pharmacologic inhibition of UBE2D3 blocks the ubiquitylation of antigen presentation-related substrates, leading to increased p-MHC presentation by cancer cells and reduced T cell exhaustion. Using immunocompetent and humanized models, we elucidate the therapeutic efficacy of targeting UBE2D3. Furthermore, we evaluate the synergistic anti-tumor effects of QX-6 in combination with KRAS-targeted TCR-T cell immunotherapy. In summary, our study reveals a post-translational modification mechanism wherein the intracellular checkpoint UBE2D3 regulates the TAP2 switch to control cancer cell evasion of CTLs, presenting a potential immunotherapeutic strategy to improve PDAC treatment outcomes.

ORGANISM(S): Mus musculus

PROVIDER: GSE270097 | GEO | 2024/06/21

REPOSITORIES: GEO

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Project description:Immune evasion is an important hallmark of cancer ensured by diverse strategies, including immunosuppression and downregulation of antigen presentation. Here, to restore immunogenicity of cancer cells, we employed the minimal gene regulatory network of highly immunogenic type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen presenting cells (APCs). We showed that enforced expression of PU.1, IRF8 and BATF3 (PIB) was sufficient to induce cDC1 phenotype in 33 cell lines derived from human and mouse hematological and solid tumors. PIB gradually modified the cancer cell transcriptional and epigenetic program imposing global antigen presentation and cDC1 gene signatures within 9 days. cDC1 reprogramming restored the expression of antigen presentation complexes as well as co-stimulatory molecules at the cell surface, leading to the presentation of endogenous antigens on MHC-I, and to CD8+ T cell mediated killing. Functionally, tumor- APCs acquired the ability to uptake and process exogenous proteins and dead cells, secreted inflammatory cytokines and cross-presented antigens to naïve CD8+ T cells. Importantly, tumor-APCs were efficiently generated at the single cell level from primary cancer cells of 7 solid tumors that presented antigens to memory and naïve T-cells, as well as to activated patient-specific intra-tumoral lymphocytes. Alongside antigen presentation, tumor-APCs harboring TP53, KRAS and PTEN mutations showed impaired tumorigenicity in vitro and in vivo. Finally, using in vivo mouse models of melanoma, we showed that intra-tumoral injection of tumor-APCs promoted lymphoid infiltration, delayed tumor growth and increased survival. The anti-tumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors enabling tumor eradication. Our approach combines cDC1’s antigen processing and presenting abilities with endogenous generation of tumor antigens and serves as a platform for the development of novel immunotherapies based on endowed antigen presentation in cancer cells.

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UBE2D3 is an Intracellular Checkpoint in Pancreatic Ductal Carcinoma that Restricts CD8+ T-Cell Antitumor Immunity

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