Detailed Abstract
[Liver Oral Presentation 4 - Basic Research]
[LV OP 4-5] T-cell exhaustion determined by PD-1 expression on tumor-infiltrating CD8 t-cells in HCC patients
Shin HWANG1, Hyung-Don KIM2, Su-Hyung PARK2, Gi-Won SONG1, Seongyeol PARK2, Min Kyung JUNG2, Kyung Hwan KIM2, Sukyeong EO2, Deok-Bog MOON1, Young Seok JU2, Eui-Cheol SHIN2
1Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Korea
2Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Korea, Korea
Introduction : Phenotypic and functional characteristics of tumor-infiltrating CD8 T-cells (CD8 TILs) has not been well studied in the context of heterogeneity of exhausted T-cells and patient stratification in hepatocellular carcinoma (HCC).
Methods : We identified distinct T-cell exhaustion profiles determined by PD-1 expression levels on CD8 TILs from 48 HCC patients undergoing surgical resection by multi-color flow cytometry and RNA sequencing.
Results : CD8 TILs from HCC patients significantly overexpressed immune checkpoint receptors such as PD-1, TIM-3 and LAG-3. CD8 TILs could be further stratified into PD-1hi, PD-1int and PD-1neg subpopulations, and TIM-3 and/or LAG-3 were exclusively expressed on PD-1hi, not PD-1int, subpopulation. RNA expression profiles were distinct among PD-1hi, PD-1int and PD-1neg CD8 TILs and a gene module of T-cell exhaustion was significantly enriched in PD-1hi CD8 TILs. HCC patients could be classified into two distinct subgroups based on the proportion of PD-1hi CD8 TILs; High PD-1 expressers and Low PD-1 expressers. High PD-1 expressers had more severely dysfunctional CD8 TILs with exhaustion profiles that were observed in PD-1hi CD8 TILs, compared to Low PD-1 expressers. High PD-1 expressers were associated with aggressive biologic tumor features. Combination blockades of Tim-3 or LAG-3 in addition to PD-1 blockade further enhanced proliferative responses of CD8 TILs from High PD-1 expressers.
Conclusions : CD8 TILs displayed heterogeneous exhaustion profiles determined by differential PD-1 expression levels in HCC patients. A certain subgroup of HCC patients expressing multiple immune checkpoint receptors appears to be eligibly indicated for immune checkpoint inhibitors for effective reinvigoration of anti-tumor immunity.
Methods : We identified distinct T-cell exhaustion profiles determined by PD-1 expression levels on CD8 TILs from 48 HCC patients undergoing surgical resection by multi-color flow cytometry and RNA sequencing.
Results : CD8 TILs from HCC patients significantly overexpressed immune checkpoint receptors such as PD-1, TIM-3 and LAG-3. CD8 TILs could be further stratified into PD-1hi, PD-1int and PD-1neg subpopulations, and TIM-3 and/or LAG-3 were exclusively expressed on PD-1hi, not PD-1int, subpopulation. RNA expression profiles were distinct among PD-1hi, PD-1int and PD-1neg CD8 TILs and a gene module of T-cell exhaustion was significantly enriched in PD-1hi CD8 TILs. HCC patients could be classified into two distinct subgroups based on the proportion of PD-1hi CD8 TILs; High PD-1 expressers and Low PD-1 expressers. High PD-1 expressers had more severely dysfunctional CD8 TILs with exhaustion profiles that were observed in PD-1hi CD8 TILs, compared to Low PD-1 expressers. High PD-1 expressers were associated with aggressive biologic tumor features. Combination blockades of Tim-3 or LAG-3 in addition to PD-1 blockade further enhanced proliferative responses of CD8 TILs from High PD-1 expressers.
Conclusions : CD8 TILs displayed heterogeneous exhaustion profiles determined by differential PD-1 expression levels in HCC patients. A certain subgroup of HCC patients expressing multiple immune checkpoint receptors appears to be eligibly indicated for immune checkpoint inhibitors for effective reinvigoration of anti-tumor immunity.
SESSION
Liver Oral Presentation 4
Room C 3/31/2018 8:30 AM - 9:20 AM