Lead researcher
Dakang Xu and Ying Le
Main finding
Characterizing immune phenotypes in human gastric cancer tissues via multiplexed immunohistochemistry (mIHC) may help guide PD-L1 clinical therapy. Observing unique disease tissue microenvironments can improve our understanding of immune phenotypes and cell interactions within these microenvironments, providing the ability to predict active responses to immunotherapies.
Centre
Centre for Cancer Research
Research group
Cancer and Innate Immunity
Journal and article title
Most surprising
We developed a novel more than 4-color mIHC assay based on tyramide signal amplification that allowed us to reliably interrogate immunologic checkpoints, including programmed death-ligand 1 (PD-L1), cytotoxic T cells (CD8+T) and regulatory T cells (Foxp3), in formalin-fixed, paraffin-embedded tissues of human gastric cancer. Surprisingly, patient stratification based on each one of these markers individually did not show significant prognostic value on patient survival. Conversely, combination of the ratios of CD8/FOXP3 and CD8/PD-L1 enabled the identification of patient subgroups with different survival outcomes. As such, high densities of PD-L1 in patients with high CD8/FOXP3 and low CD8/PD-L1 ratios correlated with increased survival. The results were also validated by the RNA-seq data in TCGA datasets.
Future implications
The tumor immune microenvironment is essential to the response of tumor cells to immunotherapy, with tumor-infiltrating immune cells negatively correlating with disease progression and treatment failure. Therefore, understanding how the landscape of tumor-infiltrating immune cells arises is very important to stratify patients which will benefit from immunotherapy. We recently reported the use of immunophenotyping of the tumor microenvironment relying on multi-marker fluorescence staining of tissues combined with unsupervised hierarchical clustering analysis, to determine the interaction between tumor cells and immune cells within the tumor microenvironment. In current project we are relying on the integration of next-generation sequencing of tumor microenvironment, with mutational profile, neoepitopes load, microsatellite instability(MSI-H), mismatch repair(MMR), and immune signals such as that elicited by Interferon (IFN) pathway that are involved in tumor-infiltrating immune cell activation; we will analyze PD-L1 levels and infiltrating immune cells in tissue microarrays (TMA) using mIHC, yielding insights into how tumor cells evade immune regulation; finally, we will use the novel biomarkers identified in our studies to establish an immune assessment scoring system, facilitating prediction of the prognosis of cancer patients, and the identification of their suitability for immunotherapy.
Disease/health impact
gastric cancer
