Dr. Bakalar is developing new methods to discover the millions of interactions between T-cell receptors and foreign antigens that trigger an immune response. In many cancers, such as metastatic melanoma, immunotherapy depends on the ability of T cells to recognize and respond to tumor-specific neoantigens—new proteins found on cancer cells, which let the immune system know that these are not normal cells. Collecting the data on this relationship can help create computational models to predict the antigen-target of a patient’s individual T cell receptor, which could then guide the design of patient-specific cancer vaccines and engineering of new, tumor-targeting T cells.

Immunotherapies that rely on reinvigorating T cells to patrol the body, detect cancerous cells and eliminate them have shown the potential for long-lasting cures. Despite their initial success, immunotherapies have been effective only for some cancers and for some patients. To improve outcomes, Dr. Birnbaum has developed a new method to match T cells with their antigen targets on cancer cells by engineering viruses to use T cell recognition as a means of cell entry. This technology will be applicable to a wide range of cancers, including ones for which immunotherapy is not currently effective.

Dr. Bonny is studying the signal pathways and molecular cues that coordinate the transition from inflammation to tissue repair in response to acute skin injury. During wounding, cells collectively activate stress response programs to promote repair and survival. Dr. Bonny is adapting and developing novel tools to map how cells leverage signaling to enable precise coordination between several different cell types in the same area. Previous work has shown a striking similarity between these stress response programs and squamous cell carcinoma tumorigenesis, suggesting this skin cancer utilizes similar pathways. Understanding how healthy tissue implements this transition may shed light on how squamous cell carcinoma and other cancers hijack and ultimately exploit these signaling mechanisms.

Dr. Chudnovskiy studies “antigen presentation,” an immune process by which dendritic cells capture antigens at the tumor site, migrate to the tumor-draining lymph nodes, and present tumor antigens to the effector CD4 and CD8 T cells that are responsible for anti-tumor responses. This is the first crucial step in successful cancer immunotherapy.

Dr. Cissé 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.

Immunotherapy has resulted in positive outcomes for patients with melanoma, lung cancer, and other malignancies; however, most patients do not have meaningful responses to this treatment strategy. Tumors that fail to respond to immunotherapy have effectively hidden themselves from detection by the host immune system. Understanding how cancers create an immune-excluded environment promises to lead to the development of more highly effective immunotherapies. Dendritic cells (DCs) play a central role in orchestrating the immune response to cancers by enabling T cells to “see” and destroy cancerous cells. Previous work has shown that melanomas secrete a protein called Wnt5a that potently suppresses DC function and ultimately contributes to the development of immunotherapy resistance. Dr. DeVito will examine certain tumor signaling pathways that have been implicated in driving Wnt5a production and facilitating cancer spreading by suppressing DC function within nearby draining lymph node tissues, which are critical for generating immune responses capable of destroying developing cancers. These studies will further investigate the ability of Wnt5a inhibition to sensitize cancers that are typically resistant to immunotherapy strategies. In addition, he is conducting a clinical trial to determine if the activation of these pathways correlates with immunotherapy failure in melanoma patients. He anticipates that better characterization of pathways that cancers utilize to suppress DC function to thus shut down the immune response will lead to the discovery of novel, more effective immunotherapy strategies, and may identify biomarkers that will improve selection of tailored immunotherapies for specific cancer patients.

Dr. Gihana investigates the role of cellular morphology in mediating the oncogenic signaling of the gene RAS in pancreatic cancer. RAS is altered in more than 30% of human cancers, making it one of the genes most affected by cancer-causing alterations. Oncogenic RAS induces pronounced changes in cell morphology. Dr. Gihana aims to understand how the changes in cell morphology contribute to the potential of RAS to cause cancer. Because direct inhibition of oncogenic RAS has been difficult to achieve, these studies of other cellular parameters that mediate RAS impact on cancer is likely to contribute to novel and effective therapies.

Dr. Gola is investigating how tissue regenerates the right cell type, at the right place. Effective cell-cell communication and cell-spatial organization are critical to maintaining organ function and homeostasis. Dr. Gola will use skin as a model tissue to understand how immune cells are organized and how they communicate with resident stem cells while maintaining tolerance and providing protection. When these interactions are disrupted, they can lead to cancers and other hyper-proliferative disorders. Unraveling the mechanisms that govern healthy immune-stem cell crosstalk and what goes wrong in disease may lead to new therapeutics for skin cancers.

Immune checkpoint inhibitors (ICI), like anti-PD-1 therapy (αPD-1), have transformed clinical oncology by inducing long-term remissions, even in metastatic disease. However, fewer than 40% of cancer patients achieve such long-term remission with αPD-1, and immune-related toxicity limits more aggressive combined approaches, such as anti-PD1 and anti-CTLA-4 therapy. The question remains why a large portion of the immune response generated by combination immunotherapy is directed towards toxicity rather than anti-tumor immunity. A better understanding of the T-cell response to ICI is needed to develop safer and more effective treatment strategies. In humans, CD8+ T-cells are responsible for anti-tumor immunity. Dr. Huang is investigating the immune responses of different types of CD8+ T-cells to αPD-1 and whether they play a role in determining clinical efficacy and immune toxicity.

Immune checkpoint inhibitors, a standard of care for metastatic melanoma, release the brakes on a patient's T cells, so they can attack a tumor. Some patients, however, relapse when resistance to treatment occurs. Dr. Kalbasi will lead a clinical trial to test a new immunotherapy treatment approach for patients with this deadly skin cancer, who did not respond to standard therapies. He will identify patients whose melanoma tumor cells express a protein called IL13Ra2. He will then collect the patient's immune T cells, engineer them to identify tumor cells that express the protein and reinfuse the T cells to kill tumor cells inside the patient. In contrast to immune checkpoint inhibitors that require regular intravenous doses, these engineered chimeric antigen receptor (CAR) T cells are a one-time treatment that theoretically protect the body for life. This clinical trial may also offer insights on how CAR T therapy overcomes tumor resistance mechanisms to treat patients with metastatic melanoma.