Study for Investigating the Mechanism of Cancer Cells on Exhausting Immunological Cells and Detected by a Real-Time Nuclear Imaging Platform

Cancer is still a leading cause of death worldwide, particularly lung cancer, head and neck cancer, and liver cancer with higher prevalence and mortality that is higher than other cancers. Cancer cells not only grow uncontrollably, but also express immune check points to suppress immune system, such as expression of PD-L1 in cancer cells binds to PD-1 in CD8+ T cells and leads to exhaustion of CD8+ T cells. However, the molecular mechanism of cancer cells on exhausting CD8+ T cells remains unclear totally. Moreover, the immunotherapy-derived drug resistance in lung cancer is needed to understand. This study hypothesizes that cancer cells inhibits the immunocytotoxic ability of CD8+T cells, resulting in the tumor growth and development. Therefore, we will investigate the potential mechanism of cancer cells on exhaustion of CD8+ T cells using biomedical techniques. We will also develop the clinical technologies for monitoring the CD8+ T cell activity against tumors based on the finding results. Our preliminary results demonstrated that smoking volunteers (nicotine) and tumor patients exhaust the anti-tumor activity of CD8+ T cells through down-regulating IL2RB expression, that leading to reduction of secreted granzyme B and perforin. This study intends to uncover the detailed mechanism for developing a real-time nuclear imaging platform to measuring the anti-tumor activity of CD8+ T cells. The physicians can further select the accuracy immunotherapeutic agents against tumors according the monitoring results in order to improve the patient’s survival rate in hospitals. There will 4 aims will be achieved in this study. At first, (1) we will validate the anti-tumor effect of CD8+ T cells against lung cancer, head and neck cancer, and liver cancer. (2) We will investigate the mechanism exhausting CD8+ T cells in tumor patients. (3) We will investigate IFNr-regulatory genes in tumor cells, and validate the roles of genes exhaust CD8+ T cells. (4) We will develop a clinical granzyme B (GZMB) radioactive imaging agent for determining the in vivo CD8+ T cell activity against cancers. This study will clarify the cellular mechanism of cancer cells on exhaustion of CD8+ T cells, and understand the immunotherapy-derive drug resistance in patients with immunotherapies. The measurement of the targeted inhibitory receptors on CD8+ T cells and development of GZMB-targeted nuclear imaging agent will help develop patient’s precision immunotherapy against cancers.

Project ID:PC10906-0023
External Project ID:MOST109-2314-B182-011