Understanding Memory T-Cell responses to cancer and the role of microbiome.

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Project Summary/Abstract: In the past decade, checkpoint blockade immunotherapies have greatly improved the overall survival of advanced melanoma patients. However, these therapies have failed to treat many other cancer types, including cancers of the pancreas, liver, and stomach. Understanding the successful tumor protective immune responses in long term cancer survivors could promote the understanding of anti-tumor immune responses and the development of novel therapeutic strategies. Melanoma patients who developed dermal immune-related adverse events (irAEs), including rash and vitiligo, have better overall survival than those unaffected patients. However, the immune mechanisms linking dermal irAEs with exceptional anti-tumor immunity remain unknown. Thus, specific aim 1 will comprehensively characterize the phenotype, persistence, antigen specificity, and localization of anti-tumoral T cell responses in both vitiligo and rash affected melanoma survivors using single-cell RNA-seq, single-cell TCR-seq, bulk TCR-seq and 10X spatial transcriptomics. I hypothesize that compared to unaffected melanoma patients, dermal irAE patients maintain more durable proinflammatory T cell responses with a more tumor-focused TCR repertoire. This project will be conducted at the Norris-Cotton Cancer Center (NCCC), well supported by a collaborative team including medical oncologist, surgeon, dermatologist and immunologist. The Sponsor’s lab houses expertise in tumor immunology, memory T cell and translational research and the sponsor has rich experiences in mentoring graduate students. The trainings will be focused on knowledge and novel technical skills such as the 10X spatial transcriptomics to successfully finish the research project. In addition, developing professionals for the transition to the K00 phase is also an important training objective. Transitioning to the K00 phase, the research focus will be cancer immunotherapy resistance mechanisms and the development of novel immunotherapeutic strategies that leverage microbiome. Intratumoral microbiomes were recently found to promote successful tumor immunity even in ‘immune-cold’ cancer types, yet the exact molecular and cellular mechanisms remain unknown. I hypothesize that certain microbiomes could reprogram immune cells and the tumor cells themselves, leading to a more proinflammatory anti-tumor microenvironment. The research will be conducted in an outstanding cancer immunology lab combining leaderships in both translational human research and mechanistic fundamental studies in pre-clinical models. The research trainings will be focused on using mouse models, genomics, epigenomics, metabolomics and cellular immunology approaches to identify the critical mechanisms to overcome immunotherapy resistant cancer growth. The goal by the end of the F99/K00 trainings is to understand the features of tumor protective immune responses and the optimal design of novel cancer immunotherapies. These trainings will provide critical knowledge and skills for the ultimate career goal to establish a research group in academia focusing on developing successful immunotherapeutic regimens.