Immunotherapy has demonstrated promise in the treatment of cancer. Unfortunately, immunotherapies are not effective for most cancer patients. One of the aspects that is considered to play an important role in this is the presence of immunosuppressive cells in the tumor, such as pro-tumoral macrophages and regulatory T cells (Tregs). Previous studies have demonstrated that the metabolism of these immune cells is associated with their phenotype and suppressive activity. Decreasing or reprogramming these cells could make cancer immunotherapies also effective for those patients who now do not respond to this treatment.
This PhD project of Ana Vizcaino Castro therefore aimed to study if pro-tumoral macrophages and Tregs could be reprogrammed by targeting their metabolism. We studied the effects of several metabolic drugs that are either FDA-approved or already being studied clinically.
The findings demonstrated that human macrophages treated with a drug that impairs glutamine metabolism inhibited the acquisition of an anti-inflammatory phenotype and gained tumor cytotoxic activity. We also found the differentiation of naïve T cells towards Tregs could be inhibited by Metformin; a common drug used for diabetic patients. And, a drug that specifically targets glutamine metabolism decreased the number of Tregs and the expression of a critical immunosuppressive marker.
In conclusion, this thesis presents studies that demonstrate that targeting the metabolism of immune suppressive cells can modify their phenotype and functions towards a less immunosuppressive type, thereby alleviating the immune suppression in the tumor. Thus, targeting tumor-associated immunosuppressive cells with specific metabolic drugs seems a promising strategy to improve the efficacy of current cancer immunotherapies.
