Developing Therapies that Mimic Caloric Restriction for Melanoma Control

Why This Research Matters
Solid tumors comprise 90% of adult cancer cases. This includes malignant melanoma, which is the fifth most common cancer in the United States and accounts for the majority of skin cancer deaths. Adoptive cell therapy is a promising cancer treatment that uses a patient’s own immune cells (T cells) to attack tumors. While this approach can eliminate solid tumors in some patients, it often fails because the tumor environment weakens T cells and prevents them from surviving long enough. Finding solutions to help therapeutic T cells survive is an unmet need in cancer treatment.  

What We Are Studying
Our research demonstrates that caloric restriction (reducing calorie intake without malnutrition) significantly improves the survival and effectiveness of therapeutic T cells in mice, leading to long-term control of aggressive melanoma tumors. We aim to understand how this works so that it can eventually be used to improve cancer therapies in humans. In our studies, caloric restriction helped T cells modulate cellular stress and interact with their surroundings. A key receptor we identified helped T cells respond to extracellular matrix (ECM), a structural component found in tumors. When we deleted this receptor from T cells, the benefits of caloric restriction disappeared. We also found that this receptor impacts the ability of T cells to produce energy and modulate stress, both of which are critical for their function. Additionally, caloric restriction increased the ability of T cells to take up defined nutrients as an energy source, which may further support their activity in tumors.  

How the Study Works
Here, we will investigate whether specific types of ECM helps activate T cell receptors to improve their survival and cancer-fighting ability. To do this, we will conduct experiments using cell cultures and in mice that have been modified to lack this form of ECM. We will also explore what signals activate the receptor on T cell that are induced by caloric restriction, and test increasing these receptors in T cells can improve their ability to control tumors, even without additional treatments. Next, we will examine how the receptors we identified helps T cells cope with stress internally. We will study how the receptors modulate this stress and whether it enables T cells to use defined nutrients as an energy source.  

Expected Impact
Using advanced metabolic testing, we will determine whether receptors improve T cell survival by boosting their energy production. This discovery opens the door to new treatment strategies. In particular, we show that approaches inspired by calorie restriction can make cancer-fighting T cells more powerful. These strategies mimic the beneficial effects of eating fewer calories without requiring people to change their diet. When combined with immunotherapy, these methods could make the treatment of melanoma more effective.