Abstract
Cytolytic activity score (CYT), defined by granzyme A and perforin expression, is a useful marker for underlying immunity. We hypothesized that CYT-high hepatocellular carcinomas (HCCs) have stronger immunogenicity and favorable tumor microenvironments, which would result in better clinical outcomes, using the cancer genome atlas (TCGA) cohort with 371 patients with HCC. We found CYT-high HCCs were associated with higher expressions of the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3), well-known mutagenic enzymes. Further, higher numbers of anti-cancer immune cells, such as CD8+ T cells and M1 macrophages, were infiltrated in CYT-high HCCs. Major T cell exhaustion markers were expressed significantly higher in CYT-high HCCs, likely as a negative feedback loop. Additionally, CYT-high HCCs strongly enriched gene sets related with enhanced immune activity. With strong immunity, patients with CYT-high HCCs had significantly longer disease-specific survival (DSS) and overall survival (OS) (p = 0.03 and <0.01). Furthermore, when the OS is stratified by exhaustion marker expressions, the CYT-high/exhaustion-low group had the best and CYT-low/exhaustion-high groups had the worst OS. Lastly, high CYT was an independent protective factor for prognosis. In conclusion, CYT-high HCCs were associated with enhanced immunity and better survival. Our findings suggest that proper identification of tumor-immune microenvironments could stratify the patients for appropriate treatments.
Highlights
T cells develop stepwise and progressive loss-of-effector functions by expressing T cell exhaustion markers or “brakes to the T cells”
We found that Cytolytic activity score (CYT)-high hepatocellular carcinomas (HCCs) were associated with significantly higher expressions of APOBEC3 family members (Figure 1a)
We found that CYT-high tumors have significantly longer progression-free interval (PFI) (median interval: 30.4 months, 95% confidence intervals (CIs) (21.2–56.7), p = 0.003; Figure 5a) and disease-free interval (DFI) (median interval: 37.7 months, 95% CI (25.1– not reached (NR)), p = 0.013; Figure 5b), as well as better disease-specific survival (DSS) (median survival: 84.4 months, 95% CI (70.5–NR), p = 0.026; Figure 5c) and overall survival (OS) (median survival: 81.9 months, 95% CI (54.1–NR), p = 0.005; Figure 5d)
Summary
T cells develop stepwise and progressive loss-of-effector functions by expressing T cell exhaustion markers or “brakes to the T cells”. The identification of T cell exhaustion markers and subsequent intense investigation in cancer immunity lead to the development of immune checkpoint inhibitors (ICIs), which have revolutionized cancer treatment. Emerging evidence has revealed that anticancer efficacy of ICIs is dependent on the characteristics of the tumor microenvironment (TME), as they require functional cytotoxic lymphocytes. It is conceivable that ICIs are highly effective in the “hot” TME, since the high density of TILs recognize ample tumor specific antigens with their diverse receptors. A few predictive biomarkers for ICIs have been identified, such as a high expression of PD-L1, mismatch repair deficiency, and increased tumor mutation load [5,6,7]
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