Abstract 4562: Intra-tumor immune activity is linked to genetic diversity of tumor infiltrating lymphocyte and impact clinical outcomes in hepatocellular cancer

Abstract

Hepatocellular carcinoma (HCC) remains the second leading cause of the cancer-related death worldwide. Ongoing clinical trials with immune checkpoint inhibitors (CPIs) for HCC have revealed considerable amount of patients do not respond. Hence, to identify the responder is imminent need for immunotherapy in HCC. We aimed to examine the immune landscape of HCC, using the publically available data set The Cancer Genome Atlas (TCGA). Clinicopathological and genomic expression data in 371 patients with HCC were obtained from TCGA. CYT was defined by GZMA and PRF1 expression, and CIBERSORT and TIMER were used to evaluate intra-tumoral immune cell composition. Kaplan-Meier curve for overall survival (OS), disease free interval (DFI), progression free interval (PFI), and disease-specific survival (DSS) were obtained and Cox Progression Hazards model was used for multivariable analysis. Gene Set Enrichment Analysis (GSEA) was also conducted to analyze the gene sets enriched in CYT-High HCC patients. High CYT was associated with high levels of activated CD8+ T cells, gamma-delta T cells, M1 macrophages, and memory CD4+T cells on CYBERSORT. A similar result was also obtained on TIMER. CYT-high HCC patients had significantly improved DFI, PFI, DSS, and OS, compared to CYT-low HCC patients. The levels of immune checkpoint molecules (ICMs), including programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), PD-L2, cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), T cell immunoglobulin and mucin domain 3 (TIM3), indoleamine 2,3-dioxygenase 1 (IDO1), and IDO2, correlated significantly with CYT. High-CYT tumors showed increased somatic copy number alterations (SCNA). Gene expression of APOBEC3 family was significantly higher in high-CYT tumors compared to low-CYT tumors. T-cell and B-cell receptors was more diverse in High-CYT tumors compared to low-CYT tumors. Multivariate survival analysis demonstrated high CYT was an independent protective factor for prognosis in patients with HCC. High CYT is associated with significantly improved survival in HCC, secondary to enhanced immunity and increased cytolytic activity by T cell and M1 macrophage. Additionally, high CYT is associated with ICMs, and CYT can be a potential biologic marker for CPIs. Note: This abstract was not presented at the meeting. Citation Format: Tstutomu Kawaguchi, Li Yan, Hideo Takahashi, Qianya Qi, Xuan Peng, Kazuaki Takabe, Eigo Otsuji. Intra-tumor immune activity is linked to genetic diversity of tumor infiltrating lymphocyte and impact clinical outcomes in hepatocellular cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4562.