Heterogeneous Exhaustion Status of Tumor-Infiltrating CD8 T Cells Determines Distinct Subgroups of Hepatocellular Carcinoma Patients Hyung-Don Kim1, Gi-Won Song2, Seongyeol Park1, Min Kyung Jung1, Min Hwan Kim1,Kyung Hwan Kim1, Sukyeong Eo3, Deok-Bog Moon2, Young Seok Ju1,3, Eui-Cheol Shin1,3, Shin Hwang2 and Su-Hyung Park1,3,* 1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea; 2Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 3Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea *Corresponding Author
Background & Aims: Heterogeneity of tumor-infiltrating CD8 T cells (TILs) has not been characterized in relation to the pattern of functional exhaustion in hepatocellular carcinoma (HCC) patients. Methods: We examined the heterogeneity of exhausted CD8 TILs from surgically resected tumor tissues of 48 HCC patients by analyzing gene expression profiles, immunophenotypes, exhaustion-related transcription factors, and functional capacities using flow cytometry and RNA sequencing. Results: Based on PD-1 expression levels, CD8 TILs from HCC patients were subdivided into PD-1hi, PD-1int and PD-1neg subpopulations, and each subpopulation displayed distinct gene expression profiles. Unlike the PD-1int subpopulation, PD-1hi CD8 TILs showed a marked enrichment for exhaustion-specific genes. Furthermore, severe exhaustion features of PD-1hi CD8 TILs were evidenced by co-expression of TIM-3 and/or LAG-3, low proportions of TCF-1+, T-bethi/Eomeslow and CD127+ cells, and impaired cytokine production. Interestingly, different proportions of PD-1hi CD8 TILs led to the identification of two distinct subgroups of HCC patients that could be distinguished by the frequency of peripheral PD-1+ CD8 T cells. A subgroup of HCC patients with enrichment of PD-1hi CD8 TILs was associated with more aggressive biologic tumor features and severe T-cell dysfunction, and expressed multiple immune checkpoint receptors on CD8 TILs that were effectively reinvigorated by combined blockade of PD-1 along with TIM-3 or LAG-3. Conclusion:PD-1hi and PD-1int CD8 TILs display disparate exhaustion profiles, and the different proportions of PD-1hi CD8 TILs allow the identification of two distinct subgroups of HCC patients. A better understanding of heterogeneous T-cell exhaustion status of individual HCC patients might be required for optimal therapeutic strategies using immune checkpoint blockades.
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