Spontaneous and therapeutic immune responses in hepatocellular carcinoma: implications for current and future immunotherapies

Abstract

Hepatocellular carcinoma (HCC) represents a major health problem in the world, ranking fifth in incidence and third in cancer-related deaths. Due to the unique immunosuppressive microenvironment of the liver, HCC develops in an immunotolerant niche posing an important obstacle to immunotherapy. A number of studies, however, have shown immunogenic properties of HCC by demonstrating spontaneous adaptive immune responses during tumor formation and progression. Furthermore, studies examining immune responses during HCC therapy have revealed that conventional treatments such as surgical resection, locoregional therapy and systemic therapy with antibodies, small molecules or chemotherapy induce adaptive immune responses that contribute to therapeutic effects. These observations have provided a basis for clinical trials involving adoptive transfers of T cells or natural killer cells, peptide and dendritic cell vaccinations or, more recently, virotherapy and inhibition of co-inhibitory molecules. Here, spontaneous and therapeutic immune responses in HCC and their implication for current and future immunotherapies are discussed.

Keywords::

• adaptive immunity
• cancer vaccination
• hepatocarcinogenesis
• hepatocellular carcinoma
• immune responses
• immunotherapy

Financial & competing interest disclosure

T Wirth has received funding from the DFG (SFB/TRR77, project C2) and the Sander Foundation. 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.

Key issues

• Hepatocellular carcinoma (HCC) represents a promising tumor entity for immunotherapy that induces spontaneous immune responses during hepatocarcinogenesis and tumor progression.

• HCC develops in an immunotolerant milieu populated by numerous immunosuppressive cell populations of myeloid and non-myeloid origin that can be manipulated for HCC therapy.

• Adaptive immune responses are a common phenomenon in conventional HCC therapies and contribute to their clinical effects.

• Immunotherapy trials directed against HCC-specific tumor-associated antigens have demonstrated the clinical potential of immunotherapy yet have so far failed to prolong the overall survival of HCC patients

• Future immunotherapy will focus on combination of immunotherapy with conventional therapies, further elucidation of the mechanisms of HCC-mediated immunosuppression and the evaluation of the clinical potential of novel immunotherapeutics, such as antibodies against co-inhibitory molecules.