Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model

Abstract

Background and Aims We have established a clinically relevant animal model of hepatocellular cancer (HCC) in immune competent mice to elucidate the complex dialog between host immunity and tumors during HCC initiation and progression. Mechanistic findings have been leveraged to develop a clinically feasible antitumor chemoimmunotherapeutic strategy. Methods Intraperitoneal injection of carbon tetrachloride and intrasplenic inoculation of oncogenic hepatocytes were combined to induce progressive HCCs in fibrotic livers of immunocompetent mice. Immunization and adoptive cell transfer (ACT) were used to dissect the tumor antigen-specific immune response. The ability of the tyrosine kinase inhibitor sunitinib to enhance immunotherapy in the setting of HCC was evaluated. Results This new mouse model mimics human HCC and reflects its typical features. Tumor-antigen-specific CD8+ T cells maintained a naïve phenotype and remained responsive during early-stage tumor progression. Late tumor progression produced circulating tumor cells, tumor migration into draining lymph nodes, and profound exhaustion of tumor-antigen-specific CD8+ T cells associated with accumulation of PD-1hi CD8+ T cells and regulatory T cells (Tregs). Sunitinib-mediated tumoricidal effect and Treg suppression synergized with antibody-mediated blockade of PD-1 to powerfully suppress tumor growth and activate anti-tumor immunity. Conclusion Treg accumulation and upregulation of PD-1 provide two independent mechanisms to induce profound immune tolerance in HCC. Chemoimmunotherapy using FDA-approved sunitinib with anti-PD-1 antibodies achieved significant tumor control, supporting translation of this approach for the treatment of HCC patients.

CFHR3 is a potential novel biomarker for hepatocellular carcinoma

“…The complement system also performs to regulate varied immune responses and is an essential innate immune system which is widely involved in tumors. 23 Previous studies had focused on the role of innate immune system in the tumorigenesis and progression of hepatocellular carcinoma and other malignancies. 24,25 One of the critical complement regulators is complement factor H (CFH), which performs as part of a protein family that includes CFHL3 and five CFHR proteins.…”

Endoplasmic Reticulum Stress Causes Liver Cancer Cells to Release Exosomal miR‐23a‐3p and Up‐regulate Programmed Death Ligand 1 Expression in Macrophages

“…HCC is closely associated with immune tolerance and suppression; thus, immunotherapy may be a promising strategy against HCC. Recently, immunotherapy has been found to be effective in several types of human cancers, such as melanoma and lung cancer, but only obtained minimal beneficial effect in HCC.…”

Effect of TGF‑β1 on blood CD4+CD25high regulatory T cell proliferation and Foxp3 expression during non‑small cell lung cancer blood metastasis

“…There are numerous reports on the correlation between non-small-cell lung cancer (NSCLC) metastasis and CTCs (18,20). Additionally, the CTCs in NSCLC metastasis were reported to cause immune responses, including both proinflammatory and anti-inflammatory regulation (21,22). However, the molecular mechanism of CD4 + CD25 + Treg cell development, maturation and function in NSCLC development remains unclear.…”