Prospects and Challenges for T Cell-Based Therapies of HCC

Abstract

The scope of therapeutic options for the treatment of hepatocellular carcinoma (HCC) has recently been expanded by immunotherapeutic regimens. T cell-based therapies, especially in combination with other treatments have achieved far better outcomes compared to conventional treatments alone. However, there is an emerging body of evidence that eliciting T cell responses in immunotherapeutic approaches is insufficient for favorable outcomes. Immune responses in HCC are frequently attenuated in the tumor microenvironment (TME) or may even support tumor progress. Hence, therapies with immune checkpoint inhibitors or adoptive cell therapies appear to necessitate additional modification of the TME to unlock their full potential. In this review, we focus on immunotherapeutic strategies, underlying molecular mechanisms of CD8 T cell immunity, and causes of treatment failure in HCC of viral and non-viral origin. Furthermore, we provide an overview of TME features in underlying etiologies of HCC patients that mediate therapy resistance to checkpoint inhibition and discuss strategies from the literature concerning current approaches to these challenges.

Keywords: CAR therapy; HBV; HCV; T cell responses; chronic hepatitis; hepatocellular carcinoma; immune checkpoint inhibition; immunotherapy; treatment failure; tumor surveillance.

Figure 1

Effects of PD-1 or PD-L1 inhibition, anti-angiogenesis treatment, and combined treatment on immune cells and tumor tissue in HCC (abbreviations: ↑/↓ high/low; marker^hi/lo high/low marker expression).

Figure 2

Proposed immune-genetic classification after integrated cluster analysis of HCC and influence on the prognosis established by the Cancer Genome Atlas Research Network [109].

Figure 3

Aspects of Treg-functions in immunotherapies of HCC according to [55,79,145,147].