PD-L1, Galectin-9 and CD8⁺ tumor-infiltrating lymphocytes are associated with survival in hepatocellular carcinoma

Abstract

Novel systemic treatments for hepatocellular carcinoma (HCC) are strongly needed. Immunotherapy is a promising strategy that can induce specific antitumor immune responses. Understanding the mechanisms of immune resistance by HCC is crucial for development of suitable immunotherapeutics. We used immunohistochemistry on tissue-microarrays to examine the co-expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM and IDO, as well as tumor CD8+ lymphocyte infiltration in HCC, in two independent cohorts of patients. We found that at least some expression in tumor cells was seen in 97% of cases for HVEM, 83% for PD-L1, 79% for Gal-9 and 66% for IDO. In the discovery cohort (n = 94), we found that lack of, or low, tumor expression of PD-L1 (p < 0.001), Galectin-9 (p < 0.001) and HVEM (p < 0.001), and low CD8+TIL count (p = 0.016), were associated with poor HCC-specific survival. PD-L1, Galectin-9 and CD8+TIL count were predictive of HCC-specific survival independent of baseline clinicopathologic characteristics and the combination of these markers was a powerful predictor of HCC-specific survival (HR 0.29; p <0.001). These results were confirmed in the validation cohort (n = 60). We show that low expression levels of PD-L1 and Gal-9 in combination with low CD8+TIL count predict extremely poor HCC-specific survival and it requires a change in two of these parameters to significantly improve prognosis. In conclusion, intra-tumoral expression of these immune inhibiting molecules was observed in the majority of HCC patients. Low expression of PD-L1 and Galectin-9 and low CD8+TIL count are associated with poor HCC-specific survival. Combining immune biomarkers leads to superior predictors of HCC mortality.

Mechanism and prognostic value of indoleamine 2,3‐dioxygenase 1 expressed in hepatocellular carcinoma

“…In HCC, previous research has described the prognostic significance of T‐IDO1 expression. Unfortunately, the conclusions are contradictory, and little is known regarding the prognostic value of I‐IDO1 expression; the potential mechanism regulating T‐IDO1 expression must also be clarified . Our study explored the potential mechanism regulating T‐IDO1 expression, and the correlations of T‐IDO1 or I‐IDO1 expression with clinicopathological features and survival were also analyzed.…”

“…Based on previous studies, the features and mechanisms of IDO1 expression in HCC tumor cells remain controversial, and its prognostic value must also be clarified . In this study, we characterize IDO1 expression in both tumor cells (T‐IDO1) and inflammatory cells (I‐IDO1) in a series of 112 surgically resected HCCs.…”

Dichotomal functions of phosphorylated and unphosphorylated STAT1 in hepatocellular carcinoma

“…Clinical data of this HCC cohort have been published previously [26]. The use of patient materials was approved by the medical ethical committee of Erasmus MC.…”

Prognostic Role of High Gal-9 Expression in Solid Tumours: a Meta-Analysis

“…Many clinical studies have clarified that the expression of Gal-9 has a close association with metastasis and recurrence in solid tumours, including melanoma [10], gastric cancer [11, 12], colon cancer [13], hepatocellular cancer [14-16], pancreatic and ampullary cancer [17], lung cancer [18], bladder cancer [19], breast cancer [20], and clear cell renal cell cancer [21]. However, the consistency and magnitude of the prognostic impact of Gal-9 remains unclear.…”