Multidimensional analysis on immune microenvironment

Full Title: Multidimensional analysis on immune microenvironment in hepatocellular carcinoma- biomarker and therapeutic discovery

Major Category: Research and Disease Areas

Subcategory: Patho-tolerance

By Valerie Chew (Team Lead), Lee Yun Hua, Lim Chun Jye, Phuong Nguyen H, Samuel Chuah

Despite recent success in cancer immunotherapies, the dynamics between tumor-microenvironment (TME), tumor cells and the systemic immune system remain elusive. Our immunological analysis aims to identify and characterise important immunological components in hepatocellular carcinoma (HCC) for their potential clinical implications. Our approach consists of seamless integration of high dimensional mass cytometry by time-of-flight (CyTOF), Next-generation sequencing and multiplexed immunohistochemistry (Vectra) analysis to identify and understand the multiple immune subsets residing in the tumor, its adjacent non-tumor liver tissues and peripheral blood in patients with HCC. We recently described an immune gradient of progressively more suppressive immune subsets from the periphery, the adjacent non-tumor tissues to tumor¹. Exhausted and immunosuppressive immune subsets such as T cells with higher expression of PD-1, CTLA-4, Lag-3 and Tim-3; the regulatory-T cells; and tumor-associated macrophages demonstrated preferential enrichment within the TME. Further functional and transcriptomic characteristics of these cells showed that their phenotypes are profoundly related to the microenvironment where they reside. Likewise, HCC tumors with different etiologies, i.e. those with chronic hepatitis B infection versus non-viral-related HCC, showed distinct tumor microenvironments². Importantly, the immunomics in the peripheral blood could serve as a powerful biomarker to predict HCC patients who will response to selective internal radiation therapy (SIRT)³. The current approach provides a holistic analysis and mapped the immune landscape of tumor in unprecedented detail. It serves as a platform for the design of immunomonitoring and immunotherapy for cancers.

References:

1. Chew, V. et al. Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses. Proceedings of the National Academy of Sciences of the United States of America 114, E5900-E5909 (2017).


2. Lim, C.J. et al. Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma. Gut (2018).


3. Chew, V. et al. Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma. Gut (2018).