Isoformic PD-1-mediated immunosuppression underlies resistance to PD-1 blockade in hepatocellular carcinoma patients

Abstract

ObjectiveImmune checkpoint blockade (ICB) has improved cancer treatment, yet why most hepatocellular carcinoma (HCC) patients are resistant to PD-1 ICB remains elusive. Here, we elucidated the role of a programmed cell death protein 1 (PD-1) isoform, Δ42PD-1, in HCC progression and resistance to nivolumab ICB.DesignWe investigated 74 HCC patients in three cohorts, including 41 untreated, 28 treated with nivolumab and 5 treated with pembrolizumab. Peripheral blood mononuclear cells from blood samples and tumour infiltrating lymphocytes from tumour tissues were isolated for immunophenotyping. The functional significance of Δ42PD-1 was explored by single-cell RNA sequencing analysis and validated by functional and mechanistic studies. The immunotherapeutic efficacy of Δ42PD-1 monoclonal antibody was determined in HCC humanised mouse models.ResultsWe found distinct T cell subsets, which did not express PD-1 but expressed its isoform Δ42PD-1, accounting for up to 71% of cytotoxic T lymphocytes in untreated HCC patients. Δ42PD-1+T cells were tumour-infiltrating and correlated positively with HCC severity. Moreover, they were more exhausted than PD-1+T cells by single T cell and functional analysis. HCC patients treated with anti-PD-1 ICB showed effective PD-1 blockade but increased frequencies of Δ42PD-1+T cells over time especially in patients with progressive disease. Tumour-infiltrated Δ42PD-1+T cells likely sustained HCC through toll-like receptors-4-signalling for tumourigenesis. Anti-Δ42PD-1 antibody, but not nivolumab, inhibited tumour growth in three murine HCC models.ConclusionOur findings not only revealed a mechanism underlying resistance to PD-1 ICB but also identified anti-Δ42PD-1 antibody for HCC immunotherapy.

Machine learning-based prognostic modeling of lysosome-related genes for predicting prognosis and immune status of patients with hepatocellular carcinoma

“…In recent years, immune checkpoint inhibitors (ICIs) have improved cancer treatment, yet most patients with hepatocellular carcinoma (HCC) remain resistant to ICBs [44]. It has been reported that lysosomes can act as a major site of destruction for immune checkpoint molecules, so we analysed the correlation between risk models and immune checkpoints, and found that CD244, CD44 TNFRSF14, CD27, etc.…”

Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Strategies and Biomarkers Predicting Response and/or Resistance

“…Δ42PD-1 mRNA was found differentially expressed in various immune-related cells (higher expression in monocytes, macrophages and NK cells; lower expression on B cells, CD4 + or CD8 + T cells, and dendritic cells) and it could induce the production of several proinflammatory cytokines (TNFα, IL-6, and Il-1β) from human peripheral blood mononuclear cells and murine dendritic cells [ 107 ]. A recent study evaluated the role of Δ42PD-1 in HCC progression and resistance to nivolumab and pembrolizumab [ 68 ]. The authors demonstrated that, compared to PD-1 + T cells, tumor-infiltrating Δ42PD-1 + T cells exhibit transcriptomic features of immune exhaustion and correlate positively with HCC severity.…”

“…The Δ42PD-1 isoform was not only associated with ICIs resistance, but it could also represent a therapeutic target. Indeed, in three murine models of HCC, anti-Δ42PD-1 antibodies inhibited tumor growth [ 68 ].…”

‘Invisible’ immune checkpoint molecule causing resistance to anti-PD1 therapy in HCC

“…As of today, only antibody-based treatments have been approved to block the PD-1/PD-L1 pathway. A recent study from Tan et al published in Gut2 describes the unexpected finding that lymphocytes from patients with HCC express an alternative spliced isoform of PD-1, which contains an in-frame deletion of 14-amino acids within the exon 2 of PD-1, Δ42PD-1. Importantly, Δ42PD-1 does not interact with PD-L1/L2 and most commercially available anti-PD-1 monoclonal antibodies do not recognise Δ42PD-1.…”