Rationally combining anti-VEGF therapy with checkpoint inhibitors in hepatocellular carcinoma - PubMed (original) (raw)

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Rationally combining anti-VEGF therapy with checkpoint inhibitors in hepatocellular carcinoma

Tai Hato et al. Immunotherapy. 2016.

Abstract

Hepatocellular carcinoma (HCC) is a fatal disease with rising incidence in the world. For advanced HCC, sorafenib, a multikinase inhibitor, is the only systemic therapy with proven survival benefits. Sorafenib is a pan-VEGF receptor inhibitor, and thus many studies have focused its antivascular effects. But VEGF also acts as an immunosuppressive molecule. VEGF can inhibit maturation of dendritic cells, promote immune suppressive cell infiltration and enhance immune checkpoint molecules expression. On the other hand, potent VEGF inhibition may increase tumor hypoxia, which could hinder antitumor immunity or immunotherapy. Thus, achieving synergy when combining anti-VEGF therapy with immunotherapy may require proper polarization of the tumor microenvironment by dose titration or combination with other immunomodulating agents.

Keywords: CTLA-4; LAG-3; PD-1; PD-L1; TIM-3; VEGF; VEGFR2; hepatocellular carcinoma; immune checkpoint.

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Conflict of interest statement

Financial & competing interests disclosure

This study is supported by the National Institutes of Health (grant nos. P01-CA080124, R01-CA159258 and R21-CA139168), a National Cancer Institute/Proton Beam Federal Share Program award and the American Cancer Society (grant no. 120733-RSG-11–073–01-TBG [to DG Duda]). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

<b>Figure 1.</b>

**Figure 1.. Potential mechanisms of immune evasion in hepatocellular carcinoma.

Multiple pathways could mediate immune evasion in HCC. APC: Antigen-presenting cell; CTL: Cytotoxic lymphocyte; DC: Dendritic cell; DCreg: Regulatory dendritic cell; HCC: Hepatocellular carcinoma; MDSC: Myeloid-derived suppressor cell; NK: Natural killer; NKT: Natural killer T cell; Treg: Regulatory T cell.

<b>Figure 2.</b>

**Figure 2.. VEGF is an immunosuppressive factor.

VEGF may act as an immunosuppressive molecule via multiple mechanisms: VEGF can inhibit maturation of dendritic cells. Dendritic cells secrete 2,3-dioxygenase, which inhibits immune response; VEGF can promote the infiltration of regulatory T cell (Treg) and myeloid-derived suppressor cell (MDSC). MDSCs inhibit both antigen presentation and CD8+ cytotoxic T cell (CTL) activity; VEGF can also enhance expression of immune checkpoint molecules expression on CTLs, which suppress the activity of CTLs.

<b>Figure 3.</b>

**Figure 3.. Potential strategies to achieve synergy between anti-VEGF therapy and immune checkpoint blockade.

Appropriate dosing of anti-VEGF therapy can ‘normalize’ tumor microenvironment, which stabilizes the vasculature and does not increase hypoxia. VEGF blockade could enhance antigen-presenting cell (APC) maturation and cytotoxic T cell (CTL) activation, and reduce immunosuppressive cell function. Addition of immune checkpoint blockade could improve antigen presentation from APC to CTL and reduce exhaustion of CTLs, which could directly promote tumor elimination.

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