Monitoring Immune Checkpoint Regulators as Predictive Biomarkers in Hepatocellular Carcinoma

Abstract

The global burden of hepatocellular carcinoma (HCC), one of the frequent causes of cancer-related deaths worldwide, is rapidly increasing partly due to the limited treatment options available for this disease and recurrence due to therapy resistance. Immune checkpoint inhibitors that are proved to be beneficial in the treatment of advanced melanoma and other cancer types are currently in clinical trials in HCC. These ongoing trials are testing the efficacy and safety of a few select checkpoints in HCC. Similar to observations in other cancers, these immune checkpoint blockade treatments as monotherapy may benefit only a fraction of HCC patients. Studies that assess the prevalence and distribution of other immune checkpoints/modulatory molecules in HCC have been limited. Moreover, robust predictors to identify which HCC patients will respond to immunotherapy are currently lacking. The objective of this study is to perform a comprehensive evaluation on different immune modulators as predictive biomarkers to monitor HCC patients at high risk for poor prognosis. We screened publically available HCC patient databases for the expression of previously well described immune checkpoint regulators and evaluated the usefulness of these immune modulators to predict high risk, patient overall survival and recurrence. We also identified the immune modulators that synergized with known immune evasion molecules programmed death receptor ligand-1 (PD-L1), programmed cell death protein-1 (PD-1), and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and correlated with worse patient outcomes. We evaluated the association between the expression of epithelial-to-mesenchymal transition (EMT) markers and PD-L1 in HCC patient tumors. We also examined the relationship of tumor mutational burden with HCC patient survival. Notably, expression of immune modulators B7-H4, PD-L2, TIM-3, and VISTA were independently associated with worse prognosis, while B7-H4, CD73, and VISTA predicted low recurrence-free survival. Moreover, the prognosis of patients expressing high PD-L1 with high B7-H4, TIM-3, VISTA, CD73, and PD-L2 expression was significantly worse. Interestingly, PD-L1 expression in HCC patients in the high-risk group was closely associated with EMT marker expression and prognosticates poor survival. In HCC patients, high tumor mutational burden (TMB) predicted worse patient outcomes than those with low TMB.

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

“…Accordingly, these studies indicate CD73s may be the major source of "CD73" overexpression in HCC. In contrast, other studies (170,171) report CD73 is overexpressed in HCC and associates with poor tumor differentiation, microvascular invasion, and poor overall and recurrence-free survival (Figure 1) (170,171). NT5E-2 expression was not assessed in these studies, which is a limitation.…”

Immune landscape of hepatocellular carcinoma microenvironment: Implications for prognosis and therapeutic applications

“…Other biomarkers that are going to be investigated in the near future include the tumour mutational burden and microsatellite instability. These biomarkers have been associated with worse outcome in HCC patients 135 IDO exerts immune suppressive function in the HCC microenvironment. IDO expression is induced by anti-tumour immune response, thus representing a negative feedback mechanism that impairs immunotherapeutic approaches.…”

“…Other biomarkers that are going to be investigated in the near future include the tumour mutational burden and microsatellite instability. These biomarkers have been associated with worse outcome in HCC patients and could represent possible predictors of response under ICI treatment, as has been reported for colorectal cancer. No clinical or radiologic markers can be considered at this moment, since objective responses have been reported independently of tumour site, liver or metastasis, with or without macrovascular invasion.…”

Challenges and Opportunities in the Clinical Development of Immune Checkpoint Inhibitors for Hepatocellular Carcinoma

“…The link between higher TMB and responsiveness to PD‐1/PD‐L1 blockade is established in melanoma and NSCLC, suggesting a better predictive role than PD‐L1 expression across tumor types . Although linked to worse prognosis, the predictive role of this biomarker, TMB, for ICPI efficacy in HCC should be prospectively tested. A number of other factors may modulate responsiveness to immunotherapy, including etiology of underlying liver disease, and TIL density and composition .…”