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.
Highlights
Patients with advanced stages of hepatocellular carcinoma (HCC) face a poor prognosis
Prognosis of HCC had improved remarkably with the implementation of immune checkpoint inhibition (CPI) into the treatment schemes as we will discuss in detail
mucosal-associated invariant T (MAIT) cells recognize bacterial B vitamins such as riboflavin derivatives presented on MR1 [80], it is astonishing that MAIT cell fractions are significantly reduced in HCC tumors compared with adjacent normal tissues and that lower SLC4A10 expression in HCC correlates with poor prognosis
Summary
Patients with advanced stages of HCC face a poor prognosis. Liver cancer is the third leading cause of cancer-related mortality worldwide [1]. III trials failed to reach the predefined endpoint both for nivolumab as a first line therapy and pembrolizumab (both inhibitors of the PD-1 pathway) as second line treatment [15,16] Still, both trials confirmed an overall response rates (ORR) of 15–20% observed in the phase II trials. Among these responding patients, complete responses defined as disappearance of vital tumors were almost non-existent These clinical results show that efficacy of CPI treatment of HCC lagged behind other tumor entities, primarily metastatic melanoma (ORR 61% [17]) and Hodgkin lymphoma (ORR 87% [18]), among others [19,20]. IMbrave150 was published that combined CPI (atezolizumab, a PD-L1 checkpoint inhibitor) with inhibition of angiogenesis (bevacizumab, targeting vascular endothelial growth factor (VEGF)).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
