Projects
Melanoma-specific T cell detection
The human immune system has been refined continually throughout our evolutionary history, and, as we now appreciate, plays an important role in protecting us from cancers as they begin to develop. It is only those cancers that are able to elude or escape from the immune system that eventually cause disease. Recent work, driven by the success of immune-stimulating medications in treating melanoma, has identified that in the majority of disease-causing cancers, the immune system recognizes the malignant tissue but is unable to mount a successful response. Because the immune cells that respond to a tumor are defined by their ability to not only recognize a problem, but copy themselves so that the problem can be addressed again in the future, detecting the presence of cells that are copies of cells recognizing a melanoma is a way to assess whether there is additional melanoma present in a person. Because these cells circulate throughout the body to monitor for disease, they are detectable in blood, which presents an opportunity to monitor patients for progressive or recurrent melanoma after an initial melanoma diagnosis and surgery.
The difficulties in using these melanoma-targeted cells to monitor patients after a melanoma is found have in large part been due to the difficulty in identifying which cells are responding to melanoma. New technological advances have provided a set of tools that can be used to distinguish with more precision which cells in a person’s original melanoma biopsy are the tumor-responsive cells that may be useful for monitoring. The work we are undertaking in this project will leverage those tools to look for tumor-responsive immune cells in early melanoma biopsies, and then monitor the blood of patients over time. If our hypothesis is correct, levels of tumor-responsive cells will increase over time in the context of recurring or progressing melanoma, and will be difficult to find or entirely absent in people who have been cured of their disease.
Earlier detection and earlier treatment of melanoma will mean better results for patients – fewer surgeries, fewer side effects, longer lives – and the ability to determine with better precision which patients will benefit from therapy will result in both fewer failed treatments and a better allocation of healthcare resources.
Cutaneous immune-related adverse events
The treatment of melanoma has been significantly improved in the last ten years through the use of a new class of medications that make use of the body’s immune system. These medications, called checkpoint inhibitors (CPI), work by releasing restrictions on cancer-specific immune cells that already exist within the body, freeing these cells to attack melanoma. Unfortunately, because CPI act on all immune cells and not only those targeting cancer, they often cause side effects that are the result of immune attack against healthy parts of the body. These side effects happen in up to 90% of patients treated with CPI, often mimic recognized autoimmune diseases, and are collectively called immune-related adverse events (irAEs).
irAEs are a complex topic in the treatment of melanoma; they are a sign that CPI treatment is working, but they can cause severe or life-threatening illness, and often require that CPI treatment be stopped. The treatment of irAEs is most often accomplished with “general-purpose” anti-inflammatory therapies like steroids, which suppress many types of immune response. Because the immune responses generated by CPI are responsible for their anti-melanoma effect as well as for irAEs, treatments for irAEs that would not be likely to suppress the anti-melanoma effect are needed. Designing or choosing such treatments is currently challenging because the specific mechanisms that underlie irAEs are not well understood.
irAEs most frequently occur in the skin, where they occur in a variety of forms that resemble other kinds of skin disease. These irAE are often biopsied to help with diagnosis, and microscopic evaluation of these biopsies provides some evidence that irAE are both similar to and distinct from the “naturally occurring” rashes they resemble. This project proposes to make use of those biopsy specimens to better understand the unique features of irAE, which will both help to understand how they occur, and help us to choose the most specific treatments for irAE in order to eliminate the side effects while leaving CPI activity against melanoma intact. We propose to make use of several techniques that are particular strengths of the different investigators involved to look at which cells are contributing to irAE in the skin, what those cells are doing, and what the results of those changes are in terms of the signals that are being sent to other cells. By looking at these changes in multiple different kinds of irAEs, and comparing them to one another as well as to other kinds of skin disease that aren’t related to cancer treatment, this proposal will enable us to provide the first map of cell types and signals that cause irAEs in the skin. By using this map, doctors treating irAEs will be able to choose treatments for irAEs that are as targeted as possible, and will be less likely to impact patients’ melanoma treatments.