Early Change in the Plasma Levels of Circulating Soluble Immune Checkpoint Proteins in Patients with Unresectable Hepatocellular Carcinoma Treated by Lenvatinib or Transcatheter Arterial Chemoembolization

Immune checkpoint inhibitors, combined with anti-angiogenic agents or locoregional treatments (e.g., transarterial chemoembolization (TACE)), are expected to become standard-of-care for unresectable hepatocellular carcinoma (HCC). We measured the plasma levels of 16 soluble checkpoint proteins using multiplexed fluorescent bead-based immunoassays in patients with HCC who underwent lenvatinib (n = 24) or TACE (n = 22) treatment. In lenvatinib-treated patients, plasma levels of sCD27 (soluble cluster of differentiation 27) decreased (p = 0.040) and levels of sCD40 (p = 0.014) and sTIM-3 (p < 0.001) were increased at Week 1, while levels of sCD27 (p < 0.001) were increased significantly at Weeks 2 through 4. At Week 1 of TACE, in addition to sCD27 (p = 0.028), sCD40 (p < 0.001), and sTIM-3 (soluble T-cell immunoglobulin and mucin domain–3) (p < 0.001), levels of sHVEM (soluble herpesvirus entry mediator) (p = 0.003), sTLR-2 (soluble Toll-like receptor 2) (p = 0.009), sCD80 (p = 0.036), sCTLA-4 (soluble cytotoxic T-lymphocyte antigen 4) (p = 0.005), sGITR (soluble glucocorticoid-induced tumor necrosis factor receptor) (p = 0.030), sGITRL (soluble glucocorticoid-induced TNFR-related ligand) (p = 0.090), and sPD-L1 (soluble programmed death-ligand 1) (p = 0.070) also increased. The fold-changes in soluble checkpoint receptors and their ligands, including sCTLA-4 with sCD80/sCD86 and sPD-1 (soluble programmed cell death domain–1) with sPD-L1 were positively correlated in both the lenvatinib and TACE treatment groups. Our results suggest that there are some limited differences in immunomodulatory effects between anti-angiogenic agents and TACE. Further studies from multicenters may help to identify an effective combination therapy.

[1]  Yulei N. Wang,et al.  Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. , 2020, The New England journal of medicine.

[2]  R. Masuzaki,et al.  Different Mechanisms of Action of Regorafenib and Lenvatinib on Toll-Like Receptor-Signaling Pathways in Human Hepatoma Cell Lines , 2020, International journal of molecular sciences.

[3]  A. Tamori,et al.  Clinical significance of circulating soluble immune checkpoint proteins in sorafenib-treated patients with advanced hepatocellular carcinoma , 2020, Scientific Reports.

[4]  M. Kudo,et al.  Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Subgroup analyses from CheckMate 040. , 2020 .

[5]  N. Chalasani,et al.  Immune Checkpoint Axes Are Dysregulated in Patients With Alcoholic Hepatitis , 2020, Hepatology communications.

[6]  A. Jemal,et al.  Cancer statistics, 2020 , 2020, CA: a cancer journal for clinicians.

[7]  K. Malagari,et al.  Association of TIM-3 with BCLC Stage, Serum PD-L1 Detection, and Response to Transarterial Chemoembolization in Patients with Hepatocellular Carcinoma , 2020, Cancers.

[8]  R. Berger,et al.  Checkpoint Genes at the Cancer Side of the Immunological Synapse in Bladder Cancer , 2019, Translational oncology.

[9]  Xifeng Wu,et al.  Soluble immune checkpoint-related proteins as predictors of tumor recurrence, survival, and T cell phenotypes in clear cell renal cell carcinoma patients , 2019, Journal of Immunotherapy for Cancer.

[10]  V. Longo,et al.  Role of BRAF in Hepatocellular Carcinoma: A Rationale for Future Targeted Cancer Therapies , 2019, Medicina.

[11]  J. Shindoh,et al.  18F-Fluorodeoxyglucose Uptake in Hepatocellular Carcinoma as a Useful Predictor of an Extremely Rapid Response to Lenvatinib , 2019, Liver Cancer.

[12]  Ming Luo,et al.  Molecular targeted and immune checkpoint therapy for advanced hepatocellular carcinoma , 2019, Journal of experimental & clinical cancer research : CR.

[13]  Mohammad Hossein Khosravi,et al.  Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2017 , 2019, JAMA oncology.

[14]  V. Longo,et al.  Emerging Role of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma , 2019, Medicina.

[15]  T. Murakami,et al.  Clinical practice guidelines for hepatocellular carcinoma: The Japan Society of Hepatology 2017 (4th JSH‐HCC guidelines) 2019 update , 2019, Hepatology research : the official journal of the Japan Society of Hepatology.

[16]  V. Longo,et al.  Predictive and Prognostic Factors in HCC Patients Treated with Sorafenib , 2019, Medicina.

[17]  V. Longo,et al.  Immune system and bone microenvironment: rationale for targeted cancer therapies , 2019, Oncotarget.

[18]  M. Kudo,et al.  Nivolumab in Advanced Hepatocellular Carcinoma: Sorafenib-Experienced Asian Cohort Analysis. , 2019, Journal of hepatology.

[19]  Peng Zhang,et al.  Trends in the treatment of advanced hepatocellular carcinoma: immune checkpoint blockade immunotherapy and related combination therapies. , 2019, American journal of cancer research.

[20]  M. Kudo,et al.  Impact of Baseline ALBI Grade on the Outcomes of Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Study , 2019, Cancers.

[21]  A. Azzariti,et al.  Gene Expression Comparison between the Lymph Node-Positive and -Negative Reveals a Peculiar Immune Microenvironment Signature and a Theranostic Role for WNT Targeting in Pancreatic Ductal Adenocarcinoma: A Pilot Study , 2019, Cancers.

[22]  M. Kudo,et al.  Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. , 2019, The Lancet. Oncology.

[23]  M. Abecassis,et al.  Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases , 2019, Clinical Liver Disease.

[24]  Xiang Xu,et al.  Soluble immune checkpoints in cancer: production, function and biological significance , 2018, Journal of Immunotherapy for Cancer.

[25]  M. Kudo Systemic Therapy for Hepatocellular Carcinoma: Latest Advances , 2018, Cancers.

[26]  Chiun Hsu,et al.  Immunomodulatory Effects of Current Targeted Therapies on Hepatocellular Carcinoma: Implication for the Future of Immunotherapy , 2018, Seminars in Liver Disease.

[27]  F. Hirsch,et al.  TIM-3, a promising target for cancer immunotherapy , 2018, OncoTargets and therapy.

[28]  M. Cutolo,et al.  A circulating cell population showing both M1 and M2 monocyte/macrophage surface markers characterizes systemic sclerosis patients with lung involvement , 2018, Respiratory Research.

[29]  A. Tamori,et al.  Changes in plasma interleukin-8 and tumor necrosis factor-α levels during the early treatment period as a predictor of the response to sorafenib in patients with unresectable hepatocellular carcinoma , 2018, Cancer Chemotherapy and Pharmacology.

[30]  M. Abecassis,et al.  Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases , 2018, Hepatology.

[31]  Gisela Schwab,et al.  Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma , 2018, The New England journal of medicine.

[32]  M. Kudo,et al.  Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. , 2018, The Lancet. Oncology.

[33]  P. Schirmacher,et al.  EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. , 2018, Journal of hepatology.

[34]  M. Kudo,et al.  Immune checkpoint blockade for the treatment of human hepatocellular carcinoma , 2018, Hepatology research : the official journal of the Japan Society of Hepatology.

[35]  M. Kudo,et al.  A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC). , 2018 .

[36]  M. Kudo,et al.  Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial , 2018, The Lancet.

[37]  Alan D. Lopez,et al.  Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global Burden of Disease Study , 2017, JAMA oncology.

[38]  S. Steinberg,et al.  Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. , 2017, Journal of hepatology.

[39]  Masatoshi Kudo,et al.  Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial , 2017, The Lancet.

[40]  J. Zhao,et al.  Soluble costimulatory molecule sTim3 regulates the differentiation of Th1 and Th2 in patients with unexplained recurrent spontaneous abortion. , 2015, International journal of clinical and experimental medicine.

[41]  J. Wands,et al.  Aspartate-β-hydroxylase induces epitope-specific T cell responses in hepatocellular carcinoma. , 2015, Vaccine.

[42]  B. Sangro,et al.  Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[43]  Masao Iwata,et al.  Antitumor Activity of Lenvatinib (E7080): An Angiogenesis Inhibitor That Targets Multiple Receptor Tyrosine Kinases in Preclinical Human Thyroid Cancer Models , 2014, Journal of thyroid research.

[44]  E. Tartour,et al.  Control of the Immune Response by Pro-Angiogenic Factors , 2014, Front. Oncol..

[45]  E. Gostick,et al.  Immunodominance and functional alterations of tumor‐associated antigen‐specific CD8+ T‐cell responses in hepatocellular carcinoma , 2014, Hepatology.

[46]  I. Mellman,et al.  Oncology meets immunology: the cancer-immunity cycle. , 2013, Immunity.

[47]  S. Steinberg,et al.  Soluble CD27-Pool in Humans May Contribute to T Cell Activation and Tumor Immunity , 2013, The Journal of Immunology.

[48]  Y. Kanda,et al.  Investigation of the freely available easy-to-use software ‘EZR' for medical statistics , 2012, Bone Marrow Transplantation.

[49]  Brett Houser,et al.  Bio-Rad’s Bio-Plex® suspension array system, xMAP technology overview , 2012, Archives of physiology and biochemistry.

[50]  Pedro M. Valero-Mora,et al.  ggplot2: Elegant Graphics for Data Analysis , 2010 .

[51]  S. Kawasaki,et al.  The committee for revision of the Clinical Practice Guidelines for Hepatocellular Carcinoma , 2010 .

[52]  S. Paggi,et al.  Sorafenib in Advanced Hepatocellular Carcinoma , 2008 .

[53]  Dieter Häussinger,et al.  Sorafenib in advanced hepatocellular carcinoma. , 2008, The New England journal of medicine.

[54]  P. Twomey,et al.  Plasma glucose measurement with the Yellow Springs Glucose 2300 STAT and the Olympus AU640 , 2004, Journal of Clinical Pathology.

[55]  S. Boerner The Cytology of Soft Tissue Tumours , 2004 .

[56]  T. Schumacher,et al.  CD27 is required for generation and long-term maintenance of T cell immunity , 2000, Nature Immunology.

[57]  M. Dumont,et al.  European Association for the Study of the Liver , 1971 .

[58]  Junnian Zheng,et al.  Lenvatinib promotes antitumor immunity by enhancing the tumor infiltration and activation of NK cells. , 2019, American journal of cancer research.

[59]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[60]  P. Twomey,et al.  Limitations of the Wilcoxon matched pairs signed ranks test for comparison studies. , 2004, Journal of clinical pathology.

[61]  Ranjeny Thomas,et al.  CD40 and dendritic cell function. , 2003, Critical reviews in immunology.

[62]  J. Bruix,et al.  Prognosis of Hepatocellular Carcinoma: The BCLC Staging Classification , 1999, Seminars in liver disease.