Reprogramming of colorectal cancer cells into antigen-presenting cells to increase immunogenicity and improve anti-tumor immune response

• Applicant: Dr. Sandra Schwarz
• Subject Area: Gastroenterology ; Hematology, Oncology ; Clinical Immunology and Allergology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 549316905

The treatment of cancer with immunotherapies is very promising, as it strengthens the body's own tumor defense and the risk of severe side effects is comparably low. This is primarily a high number of mutations that lead to the synthesis of tumor-specific antigens and are thus recognized as foreign by the immune system. In addition, the presentation of these tumor antigens on the cell surface is of crucial importance for an efficient antitumor immune response. However, tumors use various mechanisms to attenuate or even completely switch off antigen presentation. By applying a reprogramming approach, however, it is now possible to change cell properties, for example their ability to present antigens. This could help to make them more accessible for immunotherapy. Through the forced expression of only three transcription factors (PU.1, IRF8 and BATF3), it is possible to convert healthy human cells, as well as tumor cells, into antigen-presenting cells thereby improving the presentation of tumor antigens.The planned project shall investigate whether the reprogramming of tumor cells into antigen-presenting cells improves the body's own immune response. For this purpose, human patient-derived tumor cell lines of colorectal carcinomas and immune cells (especially T lymphocytes) from the very same patient will be used in vitro. The tumor cell lines will be reprogrammed and a ligandome analysis will provide information on how the presented antigen repertoire changes in comparison to control cells. The reprogrammed tumor cells can then be used to stimulate T lymphocytes. Tumor cell recognition and tumor cell elimination tests are used to determine whether the activity of the T lymphocytes is enhanced by stimulation with the reprogrammed tumor cells compared to control cells. Previous studies of the tumor reprogramming approach have mostly focused on mouse melanoma models or used human cancer model systems. The planned project would be the first to investigate matched human cell populations and perform a detailed bioinformatics and functional analysis. It is also planned to use tumor cells regardless of their mutational load in order to investigate for the first time, whether the immunogenicity of tumor cells with low mutational burden can also be improved by such a treatment.

• DFG Programme: WBP Fellowship
• International Connection: Sweden
• Host: Professor Filipe Pereira, Ph.D.