Dr. Ferreira seeks to explore dietary, microbial, and metabolic strategies to treat immune-related colitis (ir-colitis), one of the most common autoimmune toxicities resulting from immunotherapy treatment. Ir-colitis results when the patient’s immune system becomes overstimulated after immunotherapy and attacks the colon, leading to diarrhea and other gastrointestinal symptoms that can result in discontinuation of potentially life-saving immunotherapy. Although ir-colitis can be treated with steroids and other immunosuppressive agents, it remains unclear whether this immunosuppression may affect treatment. Targeting the gut microbiome through dietary intervention is a promising strategy to treat ir-colitis without interfering with cancer treatment. She plans to use a mouse model of ir-colitis to study whether intermittent fasting can be used to treat ir-colitis while simultaneously improving tumor control. She will investigate the specific metabolic and gut microbial changes that are responsible for fasting’s effects on ir-colitis, with the goal of expanding non-immunosuppressive and accessible treatment options for this common immunotherapy toxicity.

Cancer cells and certain immune cells inside tumors need a lot of energy to survive and function, creating a kind of “tug-of-war” for nutrients in the tumor’s environment. However, until recently, there has not been a good way to measure how these cells use nutrients for energy inside a living tumor. To tackle this challenge, Dr. Peace developed a new technology that can track which nutrients power a key energy pathway—the TCA cycle—in both cancer cells and immune cells, directly in vivo in tumors. By uncovering these details, his work aims to improve how we design cancer treatments, especially immunotherapies that help the immune system fight cancer more effectively. This work has the potential to be relevant for all cancers. Dr. Peace received his PhD and BA from Trinity College, Dublin.

Dr. Rojek’s [Sijbrandij Foundation Physician-Scientist] research aims to identify why cellular therapies, such as CAR T cells and tumor-infiltrating lymphocytes (TILs), confer long-lasting responses for some cancer patients while others only experience transient clinical benefit. CAR T therapies have transformed the treatment landscape for patients with blood cancers, and TILs have entered wider clinical practice to treat melanoma patients. Dr. Rojek aims to identify the genetic and epigenetic differences in CAR T cells and TILs that are associated with long-lasting versus transient responses. She is also investigating how to promote “memory” formation in CAR T cells, with the goal of translating these findings to early phase trials of cellular therapies for patients with lymphoma or melanoma.

Mitochondria harbor independent genetic material known as mitochondrial DNA (mtDNA). This compact, circular molecule encodes proteins essential for the assembly of the mitochondrial electron transport chain to generate energy in form of ATP. Like nuclear DNA, mtDNA is susceptible to damage and mutations. One of the most common disease-causing aberrations of mtDNA is termed “common deletion.” This aberration disrupts mitochondrial function, resulting in neuromuscular diseases and potentially certain cancers, including colorectal cancer. Due to a lack of tools to modify the mitochondrial genome, researchers currently do not understand the mechanisms behind common deletion. Dr. Kavlashvili [Timmerman Traverse Fellow] aims to investigate by using cutting-edge molecular biology tools to edit and visualize mtDNA genomes. She will then be poised to unravel impacts of this deletion on various tissues, in order to ultimately mitigate its pathological impact. Dr. Kavlashvili received her PhD from Vanderbilt University, Nashville and her BS from University of Iowa, Iowa City.

T lymphocytes, an important component of the immune system, recognize infected or cancerous cells with great specificity, ensuring targeted elimination. These potent cells are kept in check by regulatory T cells, the guardians of the immune system. While essential for curtailing excessive inflammation and preventing autoimmunity, their immunosuppressive properties can promote the development and progression of cancer. Regulatory T cells are distinguished by the presence of a protein called Foxp3, which plays a critical role in their differentiation, function and fitness. Foxp3 deficiency results in fatal autoimmune inflammatory disease, underscoring its importance for maintaining organismal health. Despite its significance, however, the reliance of regulatory T cells on Foxp3 in disease contexts like infection and cancer remains incompletely understood. Dr. Schiepers [HHMI Fellow] will study the fate and function of regulatory T cells in these settings using mouse genetics approaches and disease models of melanoma and colorectal cancer. Dr. Schiepers received his PhD from The Rockefeller University, New York and his MS and BS from Utrecht University, Utrecht.

Dr. Zhang [Timmerman Traverse Fellow] aims to engineer T cells with synthetic cell adhesion molecules (synCAMs) to augment current approaches for immunotherapy. This project represents a fundamentally new strategy for CAR T cell engineering that could overcome tumor escape from immunotherapy across multiple forms of cancer. Understanding how synCAMs contribute to CAR T cell efficacy will provide insights beyond cytotoxic CAR T cell therapy; this work could lead to the application of synCAMs in other engineered immune cell therapies under investigation, such as CAR macrophages, CAR natural killer cells, and CAR T regulatory cells. Overall, this approach could lead to CAR T cells that are much more robust to tumor evasion and target antigen expression, and thus much more effective therapeutically. Dr. Zhang received his PhD from University of Chinese Academy of Sciences, Shanghai and his BS from Wuhan University, Wuhan.

The interaction between cancer cells and their non-malignant neighbors in the tumor microenvironment is critical for cancer progression. While certain types of cellular crosstalk within the tissue safeguard against malignancy, cancer cells are often able to exploit nearby cells to fuel tumor growth. Dr. Song [HHMI Fellow] is interested in understanding how the complex cellular communication network in the skin, namely its sensory and immunological components, contributes to the development of cutaneous squamous cell carcinoma, one of the most common skin cancers. Identifying novel neuronal and immunological interactions within the tumor microenvironment has the potential to uncover pathways regulating cancer progression and anti-tumor immunity. Dr. Song received her PhD from Yale University, New Haven and her AB from Bryn Mawr College, Bryn Mawr.

Gene expression is a complex process, and sometimes mistakes are made, resulting in the generation of aberrant or “junk” RNAs. Dr. Insco previously discovered that cellular failure to “clean up” this junk RNA can contribute to the development and progression of melanoma. Her work is now focused on targeting aberrant RNA to treat cancer. First, she will identify compounds that specifically target melanomas that are unable to clean up their junk RNAs. Second, she will investigate how immune cells can be activated to attack melanoma cells that have high levels of aberrant RNAs. Many advances in our understanding of RNA biology over the last four decades have resulted in new therapies for patients. As this area of RNA biology is almost completely unexplored, Dr. Insco anticipates that studying mechanisms of aberrant RNA oncogenesis will reveal new therapeutic strategies for patients.

Cancer immunotherapy has revolutionized the way we treat cancer; however, it is only successful in a small subset of patients. Optimally functioning CD8 T cells, the specialized killers of the immune system, are key to the success of cancer immunotherapies. While CD8 T cell function is highly influenced by their metabolism, little is understood about how metabolism changes the function of these cells. Dr. Watson hypothesizes that metabolism affects CD8 T cell function by altering how tightly its DNA is packaged (its epigenetics), leading to altered gene expression. Using a mouse model of adoptive T cell therapy, a widely used immunotherapy in humans, and epigenetic techniques, Dr. Watson proposes to uncover how metabolism influences CD8 T cell epigenetic landscapes to control their function. He plans to apply these findings to improve T cell function and enhance tumor clearance. Dr. Watson received his PhD from the University of Pittsburgh, Pittsburgh and his BS from Hope College, Holland, Michigan.

Dr. Cissé [Merck Fellow] aims to define the functional importance of nutrient sensing within the tumor microenvironment. How cells sense and adapt to the availability of nutrients in their environment is incompletely understood, but one key pathway is the signaling system anchored by the mTORC1 kinase. The mTORC1 kinase regulates cell growth and metabolism in response to nutrients such as amino acids and glucose. Aberrant mTORC1 signaling is implicated in several cancers, including melanoma, known to be heavily influenced by factors in the microenvironment such as nutrient availability. Dr. Cissé aims to understand how tumor metabolism senses and responds to varying nutrient levels, which will be essential for developing novel therapeutic targets.