TY - JOUR
T1 - Icaritin-induced immunomodulatory efficacy in advanced hepatitis B virus-related hepatocellular carcinoma
T2 - Immunodynamic biomarkers and overall survival
AU - Qin, Shu Kui
AU - Li, Qing
AU - Ming Xu, Jian
AU - Liang, Jun
AU - Cheng, Ying
AU - Fan, Ying
AU - Jiang, Jun
AU - Ye, Hao
AU - Tao, Huimin
AU - Li, Lian
AU - Zheng, Limin
AU - Wei, Zhaohui
AU - Li, Shu
AU - Meng, Kun
AU - Ye, Bin
AU - Sun, Yan
N1 - Funding Information:
We thank all patients, families, and caregivers for their support in this study. We also thank Dr Jian Peng for his kind efforts to facilitate collaborations, Chao Zhang and Zheng Yuan for their efforts in study monitoring, and Dr Hang Liu and Laingfeng Zou for biomarker study contribution. Funding resources include the National Science and Technology Major Project (2012ZX09101215), National Natural Science Foundation of China (81903093), China Postdoctoral Science Foundation (2018M643316), and Beijing Shenogen Biomedical Ltd.
Funding Information:
We thank all patients, families, and caregivers for their support in this study. We also thank Dr Jian Peng for his kind efforts to facilitate collaborations, Chao Zhang and Zheng Yuan for their efforts in study monitoring, and Dr Hang Liu and Laingfeng Zou for biomarker study contribution. Funding resources include the National Science and Technology Major Project (2012ZX09101215), National Natural Science Foundation of China (81903093), China Postdoctoral Science Foundation (2018M643316), and Beijing Shenogen Biomedical Ltd.
Publisher Copyright:
© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - Advanced hepatitis B virus (HBV)-related hepatocellular carcinoma HCC with poor prognosis is often associated with chronic inflammation, immune tolerance, and marked heterogeneity. The interleukin-6 (IL-6)/JAK/STAT3 signal pathways play multiple regulatory roles in modulating inflammation and immunity in cancers. Polarization of myeloid-derived suppressor cells (MDSCs) is involved in HBV-related immunosuppression and CD8+ T-cell activation through ERK/IL-6/STAT3. Icaritin is a small molecule that has displayed anticancer activities through IL-6/JAK/STAT3 pathways in tumor cells and immune cells including CD8+ T cells, MDSCs, neutrophils, and macrophages. This study aimed to confirm icaritin immunomodulation in advanced HBV-related HCC patients with poor prognosis. Immunomodulation of MDSCs was evaluated in BALB/c mice in vivo. Immunomodulation of serum cytokines and a panel of immune checkpoint proteins were assessed in HBV-related, histologically confirmed HCC patients. Poor prognostic characteristics included HBV infection, bulky tumors, Child-Pugh B classification, and metastasis. Clinical end-points included safety, tumor response, and overall survival (OS). Icaritin treatment-induced dynamics of serum cytokines IL-6, IL-8, IL-10, and tumor necrosis factor-α, and soluble immune checkpoint proteins TIM3, LAG3, CD28, CD80, and CTLA-4 were assessed. No grade III/IV treatment-related adverse events were observed. Time-to-progression was significantly associated with the prognostic factors. Improved survival was observed in the advanced HCC patients with dynamic changes of cytokines, immune checkpoint proteins, and immune cells. Median OS (329-565 days) was significantly correlated with baseline hepatitis B surface antigen positivity, cytokines, tumor neoantigens, and Stenotrophomonas maltophilia infection. Composite biomarker scores of high-level α-fetoprotein and T helper type I (Th1)/Th2 cytokines associated with favorable survival warrant further clinical development of icaritin as an alternative immune-modulatory regimen to treat advanced HCC patients with poor prognosis.
AB - Advanced hepatitis B virus (HBV)-related hepatocellular carcinoma HCC with poor prognosis is often associated with chronic inflammation, immune tolerance, and marked heterogeneity. The interleukin-6 (IL-6)/JAK/STAT3 signal pathways play multiple regulatory roles in modulating inflammation and immunity in cancers. Polarization of myeloid-derived suppressor cells (MDSCs) is involved in HBV-related immunosuppression and CD8+ T-cell activation through ERK/IL-6/STAT3. Icaritin is a small molecule that has displayed anticancer activities through IL-6/JAK/STAT3 pathways in tumor cells and immune cells including CD8+ T cells, MDSCs, neutrophils, and macrophages. This study aimed to confirm icaritin immunomodulation in advanced HBV-related HCC patients with poor prognosis. Immunomodulation of MDSCs was evaluated in BALB/c mice in vivo. Immunomodulation of serum cytokines and a panel of immune checkpoint proteins were assessed in HBV-related, histologically confirmed HCC patients. Poor prognostic characteristics included HBV infection, bulky tumors, Child-Pugh B classification, and metastasis. Clinical end-points included safety, tumor response, and overall survival (OS). Icaritin treatment-induced dynamics of serum cytokines IL-6, IL-8, IL-10, and tumor necrosis factor-α, and soluble immune checkpoint proteins TIM3, LAG3, CD28, CD80, and CTLA-4 were assessed. No grade III/IV treatment-related adverse events were observed. Time-to-progression was significantly associated with the prognostic factors. Improved survival was observed in the advanced HCC patients with dynamic changes of cytokines, immune checkpoint proteins, and immune cells. Median OS (329-565 days) was significantly correlated with baseline hepatitis B surface antigen positivity, cytokines, tumor neoantigens, and Stenotrophomonas maltophilia infection. Composite biomarker scores of high-level α-fetoprotein and T helper type I (Th1)/Th2 cytokines associated with favorable survival warrant further clinical development of icaritin as an alternative immune-modulatory regimen to treat advanced HCC patients with poor prognosis.
KW - HBV-related advanced HCC
KW - dynamic biomarker
KW - icaritin anticancer immunomodulation
KW - survival
UR - http://www.scopus.com/inward/record.url?scp=85091391359&partnerID=8YFLogxK
U2 - 10.1111/cas.14641
DO - 10.1111/cas.14641
M3 - Article
C2 - 32889778
AN - SCOPUS:85091391359
SN - 1347-9032
VL - 111
SP - 4218
EP - 4231
JO - Cancer Science
JF - Cancer Science
IS - 11
ER -
