Cancer Immunotherapy is the newest approach in the fight against cancer. The overall aim is to activate the patient’s own immune system against tumor cells. In previous decades, research in Cancer Immunotherapy did not provide significant breakthroughs in the clinic. However, the recent introduction of immune checkpoint inhibitors (ICI) led to a revolution in cancer treatment. ICI are antibodies releasing the brakes from the immune system (e.g. anti-PD1, anti-CTLA4) and were first shown to have survival benefit in cutaneous melanoma patients. The astonishing results gave rise to many clinical trials and ICI proved to be effective in multiple tumor types.
Despite great successes of Cancer Immunotherapy, striking differences in objective tumor responses to immunotherapies are observed both within and between tumor types. Multiple tumor types appear to be non-responsive to ICI in clinical trials. Even in tumor types with shared cellular origin, like uveal and cutaneous melanoma, responses to ICI could not be further apart; response rates in cutaneous melanoma reach up to 60%, while in uveal melanoma (UM) they do not exceed 5%.
The aim of my project was to use multiple approaches to unravel the immune landscape in UM, including RNA sequencing and spectroscopic imaging, focussing both on the tumor cells and immune cells. Among others, analyses revealed immune checkpoint expression and immune cell subset presence within the tumor microenvironment. Culture of tumor-infiltrating lymphocytes to be tested for tumor reactivity in autologous models was impeded by the very small tumor biopsies leading to an adjusted approach with fresh tissue analysis obtaining extended data on the immune landscape in primary UM. These data can be used for the development of data-based-hypothesis to overcome immune escape mechanisms specific for UM. In addition, clinical data of approximately 100 patients with metastatic UM were analyzed, showing a low but clinically relevant response rate to combined ICI. These results, together with a second publication from a different research group, impacted the current choice of treatment in patients with metastatic UM in multiple countries.
