Melanoma was the fifth most common cancer in the United States in 2018, is the deadliest form of skin cancer, and continues to rise in incidence with over 91,000 new cases estimated in the United States in 2018 alone. Melanomas are genetically heterogeneous and highly mutated tumors that exhibit striking clinical responses to immunotherapy, even in the setting of metastatic disease burden. Nevertheless, despite new advances in treatment, most patients with advanced melanoma eventually relapse and succumb to the disease. A clear understanding of what renders a tumor "immunogenic" and likely to respond to immunotherapy is currently lacking and urgently needed to better predict clinical outcomes and improve current therapies.
Previously, the Bosenberg lab developed the YUMMER1.7 mouse model of melanoma. This cell line recapitulates human melanoma histopathology, behavior, and somatic mutation burden. This thesis dissertation focuses on characterizing the immunogenicity of the YUMMER1.7 mouse model and investigating implications in human melanomas. Specifically, this thesis profiles the somatic mutation burden, potential neoantigen load, transcriptome, and T cell receptor repertoire of YUMMER1.7 tumors. This work describes the immune modulatory pathways and T cell clonal expansion characteristics trending with immunogenicity in the YUMMER1.7 mouse model and human melanomas of The Cancer Genome Atlas. Finally, this work profiles YUMMER1.7 tumors undergoing immunotherapy at a cellular level and demonstrates immune reprogramming of key components of the tumor microenvironment.
In summary, this thesis aims to characterize factors that define immunogenicity in the YUMMER1.7 mouse model of melanoma. Elucidating cellular pathways and identifying key effector cells in the tumor microenvironment involved in the anti-melanoma immune response provides a better foundation for understanding immunotherapy mechanisms. Ultimately, these findings can improve outcomes of current immunotherapy regimens as well as provide a basis for the discovery of novel therapeutic targets to harness immune surveillance in cancer.
|Advisor:||Bosenberg, Marcus W.|
|Commitee:||Kluger, Yuval, Choate, Keith, Bilguvar, Kaya, Shuch, Brian|
|School Location:||United States -- Connecticut|
|Source:||DAI-B 81/3(E), Dissertation Abstracts International|
|Subjects:||Genetics, Immunology, Bioinformatics|
|Keywords:||Bioinformatics, Cancer, Genetics, Immunotherapy, Melanoma, Single cell rna-sequencing|
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