Immunological landscape and immunotherapy of hepatocellular carcinoma

Abstract

Advanced hepatocellular carcinoma (HCC) is a serious therapeutic challenge and targeted therapies only provide a modest benefit in terms of overall survival. Novel approaches are urgently needed for the treatment of this prevalent malignancy. Evidence demonstrating the antigenicity of tumour cells, the discovery that immune checkpoint molecules have an essential role in immune evasion of tumour cells, and the impressive clinical results achieved by blocking these inhibitory receptors, are revolutionizing cancer immunotherapy. Here, we review the data on HCC immunogenicity, the mechanisms for HCC immune subversion and the different immunotherapies that have been tested to treat HCC. Taking into account the multiplicity of hyperadditive immunosuppressive forces acting within the HCC microenvironment, a combinatorial approach is advised. Strategies include combinations of systemic immunomodulation and gene therapy, cell therapy or virotherapy.

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

“…A titered dose of Ad/IL-12 was used in this study to decrease vector spillover from the injected tumors to other organs to avoid potential IL-12-associated systemic toxicity. 20 As shown in Figure 1(a), single therapy of radiation or IL-12 significantly suppressed tumor growth, the mean tumor volume on day 35 being 375 ± 47 mm 3 ( p  < 0.001) in the radiation group and 415 ± 78 mm 3 in the IL-12 group ( p  < 0.001), compared with 1,598 ± 151 mm 3 in the untreated group. Radiation therapy induced significant tumor regression in most animals ( p  < 0.001), while IL-12 at this dose caused a transient reduction of tumors at early time (between 4 and 11 days post treatment), and after this period most tumors regained exponential growth except one mouse whose tumor became undetectable.…”

“…19 To investigate whether the combination of radiation and IL-12 can induce synergistic antitumor effects against large tumors, BALB/c mice were injected subcutaneously (s.c.) with BNL-P2 HCC cells and the tumors were allowed to establish until ≥ 10 mm in diameter (volumes between 150 and 200 mm 3 ) for 14 days and then treated with the following regimens: (1) a single dose of radiation (10 Gy), (2) a single dose of adenoviral vector encoding a single-chain murine IL-12 (Ad/IL-12; 1 × 10 8 p.f.u) by intratumoral injection, (3) a combination of both radiation and Ad/IL-12 (RT/IL-12) or (4) untreated. A titered dose of Ad/IL-12 was used in this study to decrease vector spillover from the injected tumors to other organs to avoid potential IL-12-associated systemic toxicity.…”

“…Radiation therapy induced significant tumor regression in most animals ( p  < 0.001), while IL-12 at this dose caused a transient reduction of tumors at early time (between 4 and 11 days post treatment), and after this period most tumors regained exponential growth except one mouse whose tumor became undetectable. Significantly, RT/IL-12 showed a pronounced synergistic antitumor effect, leading to sustained tumor regression and suppression in most animals (complete regression in 4 of 10 mice [40%], and partial regression in 5 of 10 mice [50%]), with the mean tumor volume being 20 ± 11 mm 3 on day 35, which was dramatically smaller than that of either of the monotherapy group (both p  < 0.001). We further investigated whether RT/IL-12 can confer beneficial survival in mice with established HCC.…”

“…We further investigated whether RT/IL-12 has similar antitumor efficacy in another cancer type, the CT26 colorectal cancer. Mice bearing large s.c. CT26 tumors (volumes between 150 and 200 mm 3 ) were treated with radiation, Ad/IL-12 or a combination of both. RT/IL-12 also showed a pronounced synergistic antitumor effect, leading to sustained tumor regression and suppression in most animals (complete regression in 1 of 10 mice [10%], and partial regression in 5 of 10 mice [50%]), while either monotherapy alone only delayed tumor growth but did not induce tumor regression (Supplementary Figure.…”

“…2 HCC is an immunogenic liver lesion as evidenced by the presence of many neoantigens and intratumoral accumulation of effector T cells. 3 However, the most HCC cancer patients do not respond to immunotherapies, likely due to the multiplicity of immunosuppressive factors, which are present within the large well-established tumors and in the liver, where robust immune responses are typically suppressed. 4 It is well established that tumors employ several immunosuppressive mechanisms to suppress immune responses.…”