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Open AccessArticle

Immune Cytolytic Activity for Comprehensive Understanding of Immune Landscape in Hepatocellular Carcinoma

1
Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
2
Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
3
Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
4
Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 14263, USA
5
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
6
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
7
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
8
Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH 44195, USA
9
Lerner Research Institute and Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44195, USA
10
Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
11
Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, the State University of New York, Buffalo, NY 14260, USA
12
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
13
Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
14
Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(5), 1221; https://doi.org/10.3390/cancers12051221
Received: 19 March 2020 / Revised: 30 April 2020 / Accepted: 11 May 2020 / Published: 13 May 2020
(This article belongs to the Special Issue Human Hepatocellular Carcinoma (HCC))
Cytolytic activity score (CYT), defined by granzyme A and perforin expression, is a useful marker for underlying immunity. We hypothesized that CYT-high hepatocellular carcinomas (HCCs) have stronger immunogenicity and favorable tumor microenvironments, which would result in better clinical outcomes, using the cancer genome atlas (TCGA) cohort with 371 patients with HCC. We found CYT-high HCCs were associated with higher expressions of the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3), well-known mutagenic enzymes. Further, higher numbers of anti-cancer immune cells, such as CD8+ T cells and M1 macrophages, were infiltrated in CYT-high HCCs. Major T cell exhaustion markers were expressed significantly higher in CYT-high HCCs, likely as a negative feedback loop. Additionally, CYT-high HCCs strongly enriched gene sets related with enhanced immune activity. With strong immunity, patients with CYT-high HCCs had significantly longer disease-specific survival (DSS) and overall survival (OS) (p = 0.03 and <0.01). Furthermore, when the OS is stratified by exhaustion marker expressions, the CYT-high/exhaustion-low group had the best and CYT-low/exhaustion-high groups had the worst OS. Lastly, high CYT was an independent protective factor for prognosis. In conclusion, CYT-high HCCs were associated with enhanced immunity and better survival. Our findings suggest that proper identification of tumor-immune microenvironments could stratify the patients for appropriate treatments. View Full-Text
Keywords: hepatocellular carcinoma; cytolytic activity; tumor infiltrating lymphocyte; TCGA hepatocellular carcinoma; cytolytic activity; tumor infiltrating lymphocyte; TCGA
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MDPI and ACS Style

Takahashi, H.; Kawaguchi, T.; Yan, L.; Peng, X.; Qi, Q.; Morris, L.G.; Chan, T.A.; Tsung, A.; Otsuji, E.; Takabe, K. Immune Cytolytic Activity for Comprehensive Understanding of Immune Landscape in Hepatocellular Carcinoma. Cancers 2020, 12, 1221.

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