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‘Invisible’ immune checkpoint molecule causing resistance to anti-PD1 therapy in HCC
  1. Tim F Greten
  1. NCI, Center for Cancer Research, Bethesda, Maryland, USA
  1. Correspondence to Professor Tim F Greten, NCI, Center for Cancer Research, Bethesda, MD 20892, USA; tim.greten{at}

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Immune checkpoint inhibitors targeting PD-1/PD-L1 have become standard of care as systemic first-line therapy for the treatment of hepatocellular carcinoma (HCC).1 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.

The investigators studied samples from a total of 74 HCC patients including 41 treatment naive patients and 33 patients treated with nivolumab or pembrolizumab and demonstrate that both HCC patients derived CD4+and CD8+ T cells express high amounts of Δ42PD-1 in contrast to T cell from healthy controls, which barely expressed any Δ42PD-1. PD-1 and Δ42PD-1 expression on T cells was mutually exclusive and the frequency of Δ42PD-1 CD8+T cells reached up to 70%. Δ42PD-1+ T cells …

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  • Contributors TFG wrote the entire manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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