Abstract 2250: UCHL1 hijacks tolerogenic DC maturation and promotes mregDC-Treg crosstalk to nullify anti-PD-L1 therapy

Abstract Background: Immune-checkpoint blockade (ICB) therapies have revolutionized cancer treatment, but such immunotherapy regimens fail in a subset of patients. Dendritic cells (DCs) are a heterogeneous group of professional antigen-presenting innate immune cells that activate adaptive immunity and determine the efficacy of immunotherapies. While they can also be hijacked by tumor-mediated factors to contribute to immune tolerance and tumor progression. However, little is known about the molecular mechanisms that drive the tolerance maturation of DCs in the tumor microenvironment (TME). Methods: We enrolled 85 patients with advanced hepatocellular carcinoma (HCC) exhibiting varying response to immunotherapy, and profiled their tumor ecosystems using a single-cell transcriptomes sequencing (scRNA-seq) and mass cytometry by time of flight (CyTOF) for 10 patients, and plasma protein level quantification, conducted both pre-treatment and post-treatment across all patients. We integrated our in-house data and 6 additional published scRNA-seq cohorts of 83 donors to generate a comprehensive landscape of cellular dynamics underlying different responses to immunotherapy. We verified the prognostic value in our in-house tumor microarray of 342 patients. Results: UCHL1 overexpression nullifies anti-PD-L1 therapy by driving conventional DC transformation into mature DCs enriched in immunoregulatory molecule (mregDC) via tolerogenic maturation and promoting mregDC and regulatory T (Treg) cell crosstalk, thereby restrains CD8+ T anti-tumor immunity. Mechanistically, UCHL1 enhances glycolysis by stabilizing HIF1α and lactate accumulation in TME, which further promotes SREBP2 activation and nuclear translocation in DCs. We verified the positive correlations of UCHL1 with HIF1α/VEGFα/LAMP3/FOXP3 in 342 patients with HCC. Genetic ablation or pharmacological inhibition of UCHL1 all reduce the mregDC and Treg accumulation, restore the immuno-surveillance of tumor-infiltrating lymphocytes, and safeguard anti-tumor immunity and efficacy of anti-PD-L1 therapy in mouse models. Conclusions: UCHL1 hijacks tolerogenic DC maturation and promotes mregDC-Treg crosstalk to nullify anti-PD-L1 therapy. Genetic ablation or pharmacological inhibition of UCHL1 unleash the immuno-surveillance of tumor-infiltrating lymphocytes, and safeguard the anti-tumor immunity. Plasma level of UCHL1 predicts the efficacy of anti-PD-L1 therapy. Citation Format: Yufei Zhao, Peiyi Xie, Qinghai Ye, Mien-Chie Hung, Hui Li. UCHL1 hijacks tolerogenic DC maturation and promotes mregDC-Treg crosstalk to nullify anti-PD-L1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2250.