Novel immunotherapeutic target for HCC: The role of Δ42PD-1

The study conducted by a group of researchers from the University of Hong Kong (HKU) has provided insight into the mechanism behind hepatocellular carcinoma (HCC) patient’s resistance to the programmed death 1 (PD-1) immune checkpoint blockade (ICB), contributing to the understanding of HCC therapy effectiveness.1 The anti-Δ42PD-1 antibody for HCC immunotherapy was also discovered, which provides the potential for cancer immunotherapy to inhibit tumor growth.1

HCC is a viral-associated cancer that disturbs the homeostasis of the immune system regulation.2,3 The prognosis of untreated HCC is unfavorable with a 1-year survival rate of <50% and a 5-year survival rate of <10%.4 It is known that factors, such as the hepatocellular growth factor (HGF), have been associated with the toll-like receptor 4 (TLR4) pathway, which is directed to tumor cells in a variety of cancer types and is highly related to tumorigenesis and progression, along with resistance to drug and ICB.1,5 This may contribute to the fact that most HCC patients are still resistant to PD-1 ICB, while ICB has led to the improvement of cancer treatment.1 Although ICB drugs, such as anti-PD-1 antibodies like nivolumab, have conflicting evidence in terms of its efficacy, it proves to have the potential as a therapy for advanced HCC.6 This study thus aimed to investigate the role of the PD-1 isoform, Δ42PD-1, in the progression of HCC and the relation to the resistance to nivolumab ICB.1

The study involved 74 HCC patients in 3 cohorts, i.e., standard curative resection alone (n=41), nivolumab + standard curative resection (n=28), and pembrolizumab + antiviral therapy (n=5).1 In the standard curative resection-alone cohort, peripheral whole blood was gathered before the surgical resection, while paired tumor and adjacent non-tumor samples were gathered after resection.1 Peripheral blood samples were collected before and after therapies in both treated groups as well.1 Samples were then analyzed using flow cytometry, immunofluorescence, single-cell ribonucleic acid sequencing (scRNA-seq), and functional studies, which involved using mice engrafted with healthy human peripheral blood mononuclear cells (PBMCs) to induce subcutaneous or orthotopic tumors for evaluating the antitumor efficacy.1

Notably, Δ42PD-1, which is unlikely to be antitumor, was shown to be highly expressed on both cluster of differentiation 4-positive (CD4-positive) and cluster of differentiation 8-positive (CD8-positive) T cells in HCC patients.1 Δ42PD-1-positive T cells were also shown to be more functionally exhausted than PD-1-positive T cells in HCC patients, which are likely related to the tumorigenic interleukin 6 (IL-6) production via TLR4 signaling.1 The frequency of Δ42PD-1-positive T cells had a negative correlation with PD-1-positive T cells and a positive correlation with HCC severity, leading to the likelihood that the differential expression of Δ42PD-1 is critically associated with HCC progression.1

Both pembrolizumab and nivolumab ICB treatments did not show any suppression of Δ42PD-1 expression, but an upregulation of Δ42PD-1 expression on T cells over time instead, which confirmed the increase of Δ42PD-1 expression during anti-PD-1 ICB.1 As such, it is likely that the distinct Δ42PD-1-positive T cells in the tumor microenvironment (TME) lead to the PD-1 blockade resistance in HCC patients, such that immunotherapy is unable to induce durable responses in approximately 80% of HCC patients.1 The overexpression of PD-1 on HCC cells instead of T cells increases tumor growth via the mammalian target of rapamycin (mTOR) signaling, while targeting this pathway with PD-1 blockade leads to better antitumor efficacy in HCC patients.1 The interaction between IL-6 on TLR4-expressing cells and Δ42PD-1-positive CD3-positive tumor-infiltrating lymphocytes (TILs) also showed that these TILs likely increase tumorigenesis via the Δ42PD-1-TLR4 axis in HCC TME and cause the TLR4 signaling in HCC, leading to inflammatory cytokine production (i.e., IL-6 and IL-8), and tumor progression.1 On the other hand, the HCC/humanized mouse models presented a limited response to nivolumab due to the lack of dendritic cells (DCs) and antitumor cytotoxic T lymphocytes (CTLs), and require a xenograft humanized model for reliable testing of ICB.1

In summary, the study has enhanced the understanding of the mechanism behind HCC patients’ resistance to PD-1 ICB.1 It has also proven the various roles that the Δ42PD-1-positive T cells play in HCC, thus paving the way towards the investigation of the potential of anti-Δ42PD-1 antibody for HCC immunotherapy.1 Retrospectively, the clinical development of a humanized anti-Δ42PD-1 antibody may be useful for HCC and other Δ42PD-1-mediated cancer treatments.1

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