Effects of UCHL1 on tolerogenic DC maturation and promotion of mregDC-Treg crosstalk to nullify anti–PD-L1 therapy.

Abstract

2605 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 tumour-mediated factors to contribute to immune tolerance and tumor progression. However, little is known about the molecular mechanisms that drive the tolerogenic 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 the 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 (TMA) of 342 patients. Results: UCHL1 overexpression nullifies anti-PD-L1 therapy by driving conventional DC transformation into mature DC 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 and lactate accumulation in TME by stabilizing HIF-1α, which further promotes SREBP2 activation and nuclear translocation in DC. We verified the positive correlations of UCHL1 with HIF-1α/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 tumour-infiltrating lymphocytes, and safeguard anti-tumour 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 tumour-infiltrating lymphocytes, and safeguard the anti-tumor immunity. Plasma level of UCHL1 predicts the efficacy of anti-PD-L1 therapy in patients with HCC. Clinical trial information: NCT04649489 .