Characterizing responsive and refractory orthotopic mouse models of hepatocellular carcinoma in cancer immunotherapy

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has a high mortality rate due to limited treatment options. Hence, the response of HCC to different cancer immunotherapies is being intensively investigated in clinical trials. Immune checkpoint blockers (ICB) show promising results, albeit for a minority of HCC patients. Mouse models are commonly used to evaluate new therapeutic agents or regimens. However, to make clinical translation more successful, better characterized preclinical models are required. We therefore extensively investigated two immune-competent orthotopic HCC mouse models, namely transplanted Hep-55.1c and transgenic iAST, with respect to morphological, immunological and genetic traits and evaluated both models’ responsiveness to immunotherapies. Hep-55.1c tumors were characterized by rich fibrous stroma, high mutational load and pronounced immune cell infiltrates, all of which are features of immune-responsive tumors. These characteristics were less distinct in iAST tumors, though these were highly vascularized. Cell depletion revealed that CD8 + T cells from iAST mice do not affect tumor growth and are tumor tolerant. This corresponds to the failure of single and combined ICB targeting PD-1 and CTLA-4. In contrast, combining anti-PD-1 and anti-CTLA-4 showed significant antitumor efficacy in the Hep-55.1c mouse model. Collectively, our data comprehensively characterize two immune-competent HCC mouse models representing ICB responsive and refractory characteristics. Our characterization confirms these models to be suitable for preclinical investigation of novel cancer immunotherapy approaches that aim to either deepen preexisting immune responses or generate de novo immunity against the tumor.

Nanoliposome C6‐Ceramide in combination with anti‐CTLA4 antibody improves anti‐tumor immunity in hepatocellular cancer

“…Thus, LipC6 in combination with αCTLA‐4 Ab can be quickly translated into the clinical application for HCC treatment. Hage et al reported that combined treatment with αPD1 Ab and αCTLA4 Ab generated the response in the transplanted Hep‐55 model, but not in the transgenic iAST model, suggesting combined blockade of PD1 and CTLA4 has a selective effect in suppressing tumor growth 41 …”

“…Hage et al reported that combined treatment with αPD1 Ab and αCTLA4 Ab generated the response in the transplanted Hep-55 model, but not in the transgenic iAST model, suggesting combined blockade of PD1 and CTLA4 has a selective effect in suppressing tumor growth. 41 We are going to further test the therapeutic efficacy of LipC6 in combination with both αCTLA4 and αPD1 Abs in HCC treatment.…”

Mouse Models of Oncoimmunology in Hepatocellular Carcinoma

“…In contrast, orthotopic models more accurately reflect the natural TME of the organ in which tumorigenesis proceeds. Hage et al characterized one such syngeneic orthotopic model involving hepatic implantation of Hep-55.1c cells (42).…”

Intrinsic Respiratory Gating for Simultaneous Multi-Mouse μCT Imaging to Assess Liver Tumors

“…μCT is also used in combination with single photon emission computed tomography (SPECT) and positron emission tomography (PET) to provide anatomical information. However, standalone μCT is also widely used due to its fast acquisition time, high spatial resolution resulting in accurate anatomical information, relatively simple image analysis, and diverse application possibilities ( 1 – 3 ).…”

“…Now-a-days, it is the prevailing liver cancer with increasing incidence ( 4 ). Multiple HCC mouse models are used preclinically to assess the treatment response of new drugs ( 1 ). For example, Hage et al ( 1 ) characterized two HCC models, investigated their response to immune checkpoint blockers (anti-PD-1and anti-CTLA-4), and determined the orthotopic tumor growth by in vivo μCT imaging.…”