Modeling the Metabolic Competition between Immune and Cancer Cells in the Tumor Microenvironment

Immunotherapy, based on enhancing the natural anti-tumor defense provided by the immune system, is a promising therapeutic approach against cancer. However, its success is compromised by the impaired metabolic fitness of immune cells upon entering the tumor microenvironment, which prevents them from killing the cancer cells. Identifying the mechanisms responsible for this impaired metabolic fitness is crucial to improve the response rates to immunotherapy. In my project, I will use a unique multidisciplinary approach to identify:

1. how different microenvironment factors limit immune-cell fitness
2. which metabolic advantages allow cancer cells to adapt to this immune-impairing environment
3. how tumor metabolism can be linked to a patient’s response to immunotherapy.

To do so, I will measure the proliferation and metabolism of cancer and immune cells in response to changes in the tumor microenvironment, and integrate these data into state-of-the-art metabolic-flux models and cancer–immune interaction models. This integrative approach will provide me with a mechanistic understanding of how a dynamic tumor microenvironment limits immune-cell fitness. In the long run, my work will enable the design of strategies to overcome this limitation which, in synergy with immunotherapy, will result in more effective cancer treatments. It will also enable a stratification of patients for immunotherapy, sparing non-responding patients from potentially harmful and costly therapies.