HGF-Induced PD-L1 Expression in Head and Neck Cancer: Preclinical and Clinical Findings.

Verena Boschert,Anton Straub,Nicola Klenk,Christian Linz,Philipp Schmucker,Stefan Hartmann,Anwar Aljasem,Axel Seher,Jonas Teusch,Max Bittrich,Urs D A Müller-Richter

doi:10.3390/ijms21228770

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a widespread disease with a low survival rate and a high risk of recurrence. Nowadays, immune checkpoint inhibitor (ICI) treatment is approved for HNSCC as a first-line treatment in recurrent and metastatic disease. ICI treatment yields a clear survival benefit, but overall response rates are still unsatisfactory. As shown in different cancer models, hepatocyte growth factor/mesenchymal–epithelial transition (HGF/Met) signaling contributes to an immunosuppressive microenvironment. Therefore, we investigated the relationship between HGF and programmed cell death protein 1 (PD-L1) expression in HNSCC cell lines. The preclinical data show a robust PD-L1 induction upon HGF stimulation. Further analysis revealed that the HGF-mediated upregulation of PD-L1 is MAP kinase-dependent. We then hypothesized that serum levels of HGF and soluble programmed cell death protein 1 (sPD-L1) could be potential markers of ICI treatment failure. Thus, we determined serum levels of these proteins in 20 HNSCC patients before ICI treatment and correlated them with treatment outcomes. Importantly, the clinical data showed a positive correlation of both serum proteins (HGF and sPD-L1) in HNSCC patient’s sera. Moreover, the serum concentration of sPD-L1 was significantly higher in ICI non-responsive patients. Our findings indicate a potential role for sPD-L1 as a prognostic marker for ICI treatment in HNSCC.

Highlights

Immune checkpoint inhibitors (ICIs) were outstandingly successful in the treatment of cancer
We investigated if the hepatocyte growth factor (HGF) and soluble programmed cell death protein 1 (sPD-L1) concentrations in the serum of HdNetSeCcItnaCboluperainitniHveenNsttSsigCdaCtii.ffoTneh,rewrbeeefwotwraen,etweedne tedoxiadffmeetiernreemnditnthoeeuifPttDchoe-Lme1ffemescRtoNoffAIHCaGnIFdtropenraoPttDmei-nLe1ncoctnoacnnecnedtnrtiarftaittohinoenincisoHanGlscFoentrations of the two pstrimotuelaintesdcHoNrrSeClCatceelwl liintehs oefadcihffeorethnteorr.igins and verified if the detected changes are really specific for hepatocyte growth factor/mesenchymal–epithelial transition (HGF/Met) signaling
Results serum of Head and neck squamous cell carcinoma (HNSCC) patients differ between different outcomes of immune checkpoint inhibitor (ICI) treatment and if the concentrations of the two proteins correlate with each other

Summary

Introduction

Immune checkpoint inhibitors (ICIs) were outstandingly successful in the treatment of cancer This new form of immunotherapy emerged from the discovery that, apart from the costimulatory receptors expressed on antigen-presenting cells, receptors exist that deliver inhibitory signals to T-lymphocytes. Like the costimulatory receptors that are mandatory for the activation of T-lymphocytes, they help to constrain self-reactive T-lymphocytes and, are important checkpoints regulating the balance between self-tolerance and autoimmunity [1]. One of these checkpoints is PD-1 (programmed cell death protein 1) with its ligands PD-L1 and PD-L2 [1,2,3]. When being recognized by T-lymphocytes via binding of T-cell receptor and tumor antigen, an efficient T-cell-activation is prevented by this inhibitory immune checkpoint, and, the tumor cell is able to escape from the immune system

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