## 5 Biomarkers of Response and/or Resistance to Immune Checkpoint Inhibitors
### Markers of Response and/or Resistance Associated to the Host  
#### 5.3.1 Role of Etiology in the Prediction of Response to Immune Checkpoint Inhibitors  
Specific clinical features can influence the efficacy of immunotherapies in patients with HCC, and one of them is the etiology of the underlying liver disease. HCC etiologies (viral as compared to non-viral HCC) contribute differently in shaping the immune TME and, consequently, modulate the response to ICIs [3]. NASH-HCCs might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage and impaired immune surveillance. Indeed, an increased intrahepatic infiltration of exhausted and unconventionally activated CD8\({}^{+}\)PD1\({}^{+}\) T cells has been demonstrated in both mouse and human with NASH [67; 112]. These CD8\({}^{+}\)PD1\({}^{+}\) T cells exert cytotoxic activity against hepatocytes, resulting in neuroinflammation. Moreover, the auto-aggressive behavior of intratumoral CD8\({}^{+}\)PD1\({}^{+}\) T cells results in a loss of tumor surveillance function and in the development of a pro-tumorigenic microenvironment [112]. This auto-aggressive behavior of non-viral HCCs, and of particularly NASH-related HCCs, makes tumors less responsive to ICIs than virus-related ones [67]. In addition, immunosuppressive CXCR2\({}^{+}\) neutrophils have been recently associated with resistance to anti-PD-1 therapy in NASH-HCC patients, while CXCR2 antagonization resulted in restoration of the response to ICIs [113].  
A recent systematic review summarized the results of 49 phase III trials across all stages of HCC and investigated the relationship between etiology and outcome with various systemic therapies [60]. A meta-analysis of three trials assessing immunotherapies (CheckMate-459, IMbrave150, and KEYNOTE-240 for a total of 1656 patients) demonstrated that patients with a virus-related HCC treated with ICIs had a significantly greater OS benefit compared to the control group (HR = 0.64, 95% CI, 0.50-0.83). Instead, in non-viral patients, the survival of ICIs-treated patients was not significantly superior to that of thecontrol group (HR = 0.92, 95% CI, 0.77-1.11) [60]. Remarkably, the clinical benefit provided by ICIs was similar in HBV- and HCV-related HCC. Moreover, a separate metanalysis of five trials (REACH, REACH-2, METIV-HCC, CELESTIAL, and JET-HCC for a total of 2083 patients) did not show an impact of etiology on outcome of TKIs/anti-VEGF, as no differences in efficacy were found between the viral and non-viral HCCs (\(p\) = 0.88) [60]. Results similar to those of meta-analyses have been found in a large retrospective study including almost 1000 patients with non-viral HCC in whom, after propensity score matching, lenvatinib provided a greater benefit in OS and PFS than atezo+beva [72].  
However, differential clinical outcomes according to etiology have not been consistently reported across all immunotherapy RCTs [7; 9; 47], suggesting that the modulation of ICIs response by etiology is only partially unraveled. Moreover, although intriguing, data on this topic come from post-hoc analyses of phase III trials or retrospective studies and, as such, can be considered as \"generating hypothesis\" indications, providing a rationale to stratify patients by etiology in future trials but, for now, not supporting the choice of therapies other than ICIs for patients with non-viral HCCs in clinical practice.