Periodic Reporting for period 4 - STIMUNO (Searching for novel strategies improving cancer immunotherapy)
Okres sprawozdawczy: 2023-06-01 do 2024-11-30
Cancer immunotherapy has recently become an important component of the combination treatment schedules for patients with multiple types of cancer. However, despite spectacular clinical responses in some patients, the immunosuppressive tumor microenvironment (TME) constitutes a key barrier to effective immunotherapy. Therefore, the identification of immunosuppressive mechanisms within TME which have not been studied so far becomes the pressing subject in the field of anti-tumor immunotherapy.
The overall objective of this project is to explore novel metabolic pathways involved in the regulation of antitumor immune response. Specifically, we concentrated on amino acid metabolism in both hematological and solid tumor models. Within the tumor microenvironment, we have discovered a new metabolite with a robust ability to inhibit the activity of immune cells and their potential to kill target tumor cells. The knowledge gained so far during the implementation of this project can potentially help to design novel therapeutic approaches that could further increase response rates in cancer patients.
The overall objective of this project is to explore novel metabolic pathways involved in the regulation of antitumor immune response. Specifically, we concentrated on amino acid metabolism in both hematological and solid tumor models. Within the tumor microenvironment, we have discovered a new metabolite with a robust ability to inhibit the activity of immune cells and their potential to kill target tumor cells. The knowledge gained so far during the implementation of this project can potentially help to design novel therapeutic approaches that could further increase response rates in cancer patients.
We identified a byproduct of amino acid metabolism as an important factor limiting the activity of effector immune cells. We have documented that this metabolite can be accumulated in tumor cell cultures and tumor interstitial fluid (TIF) isolated from mice inoculated with tumor cell lines. We implemented and optimized the method of the detection of this metabolite. We have also established a method of isolation of TIF from murine tumors that enables the analysis of tumor metabolome. To elucidate the mechanisms responsible for the immunosuppressive activity of the identified metabolite, we optimized a vast array of methods to study the activity of NK cells and T cells. We observed that the selected metabolite inhibits the natural cytotoxicity of NK cells, ADCC process, TCR-mediated killing as well as CAR-mediated killing. To further identify the mechanisms of inhibition, we optimized and employed methods to study degranulation, cytokines production, and synapse formation.
During the project implementation, we managed to build a robust platform to screen the consecutive steps of recognition, activation and antitumor activity of effector immune cells. Moreover, we have optimized and implemented a wide array of assays to determine the cytotoxic potential of NK cells (in natural cytotoxicity and ADCC mechanism), T cells (via TCR-mediated activation) and CAR-modified effector cells. This complex platform is a robust tool that will enable future research and identification of various factors potentially affecting the outcome of adoptive immunotherapies and therapeutic schemes relying on the activation of T cells and NK cells.