Abstract
Tumor expression of immune co-inhibitory ligands, such as PD-L1 and Galectin-9, have potential prognostic value in Hepatocellular Carcinoma (HCC). Circulating levels of these molecules, however, have hardly been studied. This study aims to assess the prognostic significance of circulating PD-L1 and circulating Galectin-9 in patients with resected HCC, and to compare their prognostic significance to the intra-tumoral expression of these same molecules. Archived tissues and stored peripheral blood samples from 81 patients who underwent HCC resection or liver transplantation, with curative intent, were used. Immunohistochemistry was performed to determine intra-tumoral expression of PD-L1 and Galectin-9, while ELISA was used to quantify their respective circulating levels. High circulating PD-L1 (HR 0.12, 95%CI 0.16–0.86, p = 0.011) and high circulating Galectin-9 (HR 0.11, 95%CI 0.15–0.85, p = 0.010) levels were both associated with improved HCC-specific survival. Surprisingly, there was no correlation between circulating levels of PD-L1 and Galectin-9 and their intra-tumoral expression levels. In fact, circulating levels of PD-L1 and Galectin-9 were predictive of HCC-specific survival independently of intra-tumoral levels and baseline clinicopathologic characteristics. Combined analysis of circulating levels and intra-tumoral expression of PD-L1 (HR 0.33, 95%CI 0.16–0.68, p = 0.002) and Galectin-9 (HR 0.27, 95%CI 0.13–0.57, p = 0.001) resulted in more confident prediction of survival. In conclusion, circulating PD-L1 and Galectin-9 levels prognostically differentiate resected HCC patients, independently of their intra-tumoral expression. Combining circulating and intra-tumoral expression levels of PD-L1 or Galectin-9 further improves the prognostic values of these immune biomarkers.
Highlights
Worldwide over half a million people die from HCC1
Recent approval of anti-CTLA-4 and anti-PD-1 antibodies for the treatment of advanced melanoma, non-small cell lung cancer, renal cell carcinoma and bladder cancer has made it clear that immunotherapy is the new wave of anti-cancer treatments
We have previously shown that tumor PD-L1 protein expression is a promising prognostic biomarker in HCC14
Summary
Worldwide over half a million people die from HCC1. Only 20% of patients with HCC are diagnosed early enough to be candidates for curative treatments such as resection, local ablation or liver transplantation[2]. In view of the high costs and occasional severe toxicity of these novel therapies, immune specific biomarkers that can predict which patients will benefit are urgently needed Two such recent promising immune biomarkers in HCC are PD-L1 and Galectin-9 (Gal-9). Tumor PD-L1 protein expression has shown promise as a predictive biomarker to identify cancer patients that respond to anti-PD1 immunotherapy[15,16]. Gal-9 causes T-cell inhibition and apoptosis through its binding to the co-inhibitory receptor TIM-3 and blockade of the interaction between Gal-9 and TIM-3 reinvigorates ex vivo responses of T-cells of HCC and melanoma patients to tumor antigens[8,18]. In addition to cell-bound expression, soluble forms of PD-L1 and Gal-9 exist in the circulation These circulating forms of PD-L1 and Gal-9 have been poorly studied in cancer patients. No study has investigated the relationship of circulating Gal-9 to cancer survival before
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