TY - JOUR
T1 - PD-L1, Galectin-9 and CD8(+) tumor-infiltrating lymphocytes are associated with survival in hepatocellular carcinoma
AU - Sideras, Kostandinos
AU - Biermann, Katharina
AU - Verheij, Joanne
AU - Takkenberg, Bart R.
AU - Mancham, Shanta
AU - Hansen, Bettina E.
AU - Schutz, Hannah M.
AU - de Man, Robert A.
AU - Sprengers, Dave
AU - Buschow, Sonja I.
AU - Verseput, Maddy C. M.
AU - Boor, Patrick P. C.
AU - Pan, Qiuwei
AU - van Gulik, Thomas M.
AU - Terkivatan, Turkan
AU - Ijzermans, Jan N. M.
AU - Beuers, Ulrich H. W.
AU - Sleijfer, Stefan
AU - Bruno, Marco J.
AU - Kwekkeboom, Jaap
PY - 2017
Y1 - 2017
N2 - 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 CD8CTIL count were predictive of HCC-specific survival independent of baseline clinicopathologic characteristics and the combination of these markers was a powerful predictor of HCCspecific survival (HR 0.29; p P <0.001). These results were confirmed in the validation cohort (n D 60). We show that low expression levels of PD-L1 and Gal-9 in combination with low CD8CTIL 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
AB - 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 CD8CTIL count were predictive of HCC-specific survival independent of baseline clinicopathologic characteristics and the combination of these markers was a powerful predictor of HCCspecific survival (HR 0.29; p P <0.001). These results were confirmed in the validation cohort (n D 60). We show that low expression levels of PD-L1 and Gal-9 in combination with low CD8CTIL 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
U2 - https://doi.org/10.1080/2162402X.2016.1273309
DO - https://doi.org/10.1080/2162402X.2016.1273309
M3 - Article
C2 - 28344887
SN - 2162-4011
VL - 6
SP - e1273309
JO - Oncoimmunology
JF - Oncoimmunology
IS - 2
ER -