The Impact of TCR Affinity on T-Cell Dysfunction and Immunotherapeutic Reprogramming in Solid Tumors
Abstract
My goal is to become a tumor immunologist with an independent research program to decipher the complex interplay between cancer cells and immune cells and to look for opportunities to use the acquired insights to identify interventions for the treatment of human solid cancers. My proposal is ideally suited for the Immunotherapy research area of the Horizon Award, because it addresses fundamentally important questions in tumor immunology, which will reveal new mechanisms and targets for better and more effective immunotherapeutic strategies for solid cancers. Conducting this work under the mentorships of Dr. Andrea Schietinger, a highly successful and experienced basic scientist and tumor immunologist, and Dr. Jedd Wolchok, a world-renowned leader in clinical cancer immunotherapy, will poise me to successfully and productively pursue the proposed aims and to build the foundation for my future scientific career at the forefront of cancer research. Conducting my studies at Memorial Sloan Kettering Cancer Center, one of the leading institutions in cancer research and cancer immunotherapy, will provide the necessary environment, training, and education from world-leading clinicians and scientists through academic classes, seminars, symposia and collaborations, to become a leading scientist in cancer immunology. Much has been published recently about the success of cancer immunotherapy, but important to note is that though some patients respond, most patients and most tumor types either do not respond or quickly relapse. Important work is being done to build on the initial successes of immunotherapy, but I believe that it is critically important to investigate our failures -- to determine the limitations of current approaches so we can design better immunotherapies especially for patients where therapies have largely failed. Much of the success has been in treating hematologic (blood) malignancies, while immunotherapy for treating the more common solid tumors has remained challenging. Solid cancers, including breast, prostate, pancreatic, metastatic melanoma, and lung cancers are highly prevalent amongst Service men and women due to high level of exposure to environmental risk factors (e.g., radiation, ultraviolet, etc.), thus designing effective treatment regiments for solid tumors would greatly benefit active duty Service members, their families, Veterans, as well as the general public. Full realization of the immense potential of cancer immunotherapy requires a deep mechanistic understanding of the functional and molecular characteristics of immune cells that are capable of mediating successful anti-cancer responses, knowledge that is currently lacking. In this application, I aim to utilize preclinical mouse models of solid malignancies that accurately reflect human biology to understand the barriers to immunotherapy in solid tumors, design strategies to overcome them, and to ultimately work with our clinical colleagues to test and validate my findings in human disease. Cytotoxic cells of the immune system (T cells) specifically recognize cancer cells through a receptor on their surface, called the T cell receptor (TCR), which specifically binds to protein fragments (tumor antigens) presented on the surface of cancer cells. The strength of the TCR/antigen interaction (affinity) is a critical factor in tuning T cell effector function. It has been generally thought that higher affinity mediates more robust responses. However, little is known about how affinity defines T cell function in the context of solid tumors and T cell responses to immunotherapy. My proposed research program utilizes a novel in vivo tumor model system that I developed to precisely dissect the impact of affinity on T cell function in solid tumors. In this model, tumors are engineered to express antigens of defined, but distinct affinities to a specific TCR. My proposal builds on the surprising preliminary finding that high-affinity interact
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710277
Entities
People
- Mojdeh Shakiba
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army