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. 2020 Nov;111(11):4218-4231.
doi: 10.1111/cas.14641. Epub 2020 Sep 24.

Icaritin-induced immunomodulatory efficacy in advanced hepatitis B virus-related hepatocellular carcinoma: Immunodynamic biomarkers and overall survival

Shu-Kui Qin  1 , Qing Li  2 , Jian Ming Xu  3 , Jun Liang  4 , Ying Cheng  5 , Ying Fan  2 , Jun Jiang  2 , Hao Ye  6 , Huimin Tao  7 , Lian Li  7 , Limin Zheng  7 , Zhaohui Wei  8 , Shu Li  9 , Kun Meng  9 , Bin Ye  9 , Yan Sun  2
Affiliations

Icaritin-induced immunomodulatory efficacy in advanced hepatitis B virus-related hepatocellular carcinoma: Immunodynamic biomarkers and overall survival

Shu-Kui Qin et al. Cancer Sci. 2020 Nov.

Abstract

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.

Keywords: HBV-related advanced HCC; dynamic biomarker; icaritin anticancer immunomodulation; survival.

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Conflict of interest statement

SL is an ex‐employee and shareholder of Beijing Shenogen. BY and KM are employees and shareholders of Beijing Shenogen Biomedical Ltd. The other authors have no conflict of interest.

Figures

Figure 1
Figure 1
Immunomodulatory anticancer activities of icaritin in advanced hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC). Icaritin interacts with the protein complex and modulates interleukin‐6 (IL‐6)/JAK/Stat3 associated multiple immunomodulatory anticancer pathways including HBV‐related HCC immune tolerance, cytokines, immune checkpoints, immune cells, and tumor antigen α‐fetoprotein (AFP). CTLA‐4, cytotoxic T‐lymphocyte associated protein 4; IDO, indoleamine 2,3‐dioxygenase; IFN‐γ, interferon‐y; LAG3, lymphocyte‐activation gene‐3; MDSC, myeloid‐derived suppressor cell; PD‐L, programmed cell death‐ligand; Th, T helper; TIM3, T‐cell immunoglobulin mucin‐3; TNF‐α, tumor necrosis factor‐α; Treg, regulatory T cell
Figure 2
Figure 2
Kaplan‐Meier analysis of icaritin treatment‐induced time‐to‐progression and prognosis factors in advanced hepatitis B virus‐related hepatocellular carcinoma. Kaplan‐Meier analysis of time to progression with poor prognosis characteristics of portal vein tumor thrombus (A), macroscopic vascular invasion (B), Barcelona Clinic Liver Cancer (BCLC) staging (C), and α‐fetoprotein (AFP) (D). HR, hazard ratio
Figure 3
Figure 3
Dynamic changes of cytokines and Kaplan‐Meier analysis of survival in advanced hepatitis B virus‐related hepatocellular carcinoma (HCC). A1‐A4, Icaritin treatment‐induced dynamic changes of interleukin (IL)‐6, IL‐8, IL‐10, and tumor necrosis factor‐α (TNF‐α) at pre‐ (D0) and posttreatment (D56) of HCC patients of the advantage (A) group (blue lines) and the disadvantage (D) group (red lines). B1‐B4, Kaplan‐Meier survival analysis data. C1‐C4, Kaplan‐Meier analysis of overall survival (OS) of baseline levels of serum IL‐6, IL‐8, IL‐10, and TNF‐α. H, high; HR, hazard ratio; L, low
Figure 4
Figure 4
Treatment‐induced dynamics of soluble immune checkpoint proteins and survival in advanced hepatitis B virus‐related hepatocellular carcinoma (HCC). Icaritin treatment‐induced dynamic changes of serum T‐cell immunoglobulin mucin‐3 (TIM3), lymphocyte‐activation gene 3 (LAG3), CD28, CD80, and cytotoxic T‐lymphocyte associated protein 4 (CTLA‐4) at pre‐ (D0) and posttreatment (D56) of HCC patients (A1‐5) of the advantage group (blue lines) and the disadvantage group (red lines), with their Kaplan‐Meier survival analysis data (B1‐5). HR, hazard ratio
Figure 5
Figure 5
Icaritin inhibited tumor growth, infiltration of programmed cell death‐ligand 1 (PD‐L1)+ myeloid‐derived suppressor cells (MDSC) in vivo, and induced survival in hepatocellular carcinoma patients. A1‐4, Tumor growth inhibition (H22‐BALB/c mice) was correlated with the decreased immune cell infiltration of MDSC to CD45+ ratio (%) and PD‐L1+MDSC to CD45+ ratio (%), but was less correlated with PD‐L1+ MDSC to MDSC ratio (%). B1, Dual staining of PD‐L1 and CD68 in macrophages in a partial response case. B2, Kaplan‐Meier survival analysis of patients with immune cell PD‐L1 expression (cut‐off ≥ 1% tumor/immune cells). B3, Kaplan‐Meier survival analysis of patients with high expression of PD‐L1 with low and high platelet counts. C1, Neutrophil‐to‐lymphocyte ratio (NLR) in the advantage vs disadvantage group. C2, C3, Dynamic changes of NLR of 30% decrease (blue), 30% increase (red), and minor changes/stable (gray) (C2) with Kaplan‐Meier survival analysis (C3). Ctrl, control; ICT, icaritin; HR, hazard ratio; OS, overall survival
Figure 6
Figure 6
Hepatitis B virus (HBV) infection and cytokines associated with survival in advanced hepatocellular carcinoma. A, B, Correlation of baseline serum γ‐interferon (IFN‐γ), tumor necrosis factor‐α (TNF‐α), and HBV viral DNA copy number. C, D, Kaplan‐Meier survival analysis of subgroups with combination of baseline IFN‐γ/TNF‐α. E, F, Correlation of baseline serum interleukin (IL)‐6 and IL‐8 with HBV viral DNA copy number. G, H, Kaplan‐Meier survival analysis of subgroups with combination of serum IL‐6 and IL‐8. H, high; HBsAg, hepatitis B surface antigen; L, low; OS, overall survival
Figure 7
Figure 7
Kaplan‐Meier survival analysis with composite biomarker scoring (CBS) in advanced hepatocellular carcinoma. Kaplan‐Meier survival analysis of subgroups with composition biomarker scores (CBS) of α‐fetoprotein (AFP; ≥100 ng/mL), interleukin‐6 (IL‐6; <2.2 pg/mL), IL‐8 (<28.7 pg/mL), IL‐10 (<0.365pg/mL), tumor necrosis factor‐α (TNF‐α; <3.5pg/mL), and γ‐interferon (IFN‐γ; ≥5.0 pg/mL), with a score of 1 for each. Patients with CBS of AFP, IL‐6, IL‐8, IL‐10, and TNF‐α (A‐C), CBS of AFP, IL‐6, and TNF‐α (D), and CBS of IFN‐γ, TNF‐α, and IL‐6 (E, F)
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