Immunomodulatory agents are a novel class of targeted chemotherapeutic agents that modulate the immune response. These agents have shown tremendous promise as frontline and adjuvant anticancer therapeutics. The mechanism of action of these agents is thought to involve tuning the activity state of the immune system, potentially activating a previously suppressed anti-tumor response. By using the immune system to treat malignancies, oncologists have the potential to effect durable responses in populations which currently lack effective treatment options, such as those with malignant melanoma. Despite their successes, serious side effects and inconsistencies in tumor response have been reported. Understanding what genetic and immunological factors underlie the propensity of a tumor to respond to immunomodulatory therapy is therefore of pivotal importance in order to maximize the benefits of these agents. To this end I plan on characterizing the interactions between the immune system and tumor cells in a mouse model of carcinogen induced skin cancer. In this model mice develop two distinct classes of caricnomas: class A carcinomas dependent upon prolonged inflammation;and class B carcinomas which are less dependent upon prolonged inflammation. These tumor types demonstrate distinct patterns of mutation and gene expression modulation, as well as differential interactions with the immune system. By studying the genetic and immunological factors contributing to the development and progression of these tumor subtypes, as well as testing the efficacy of the immunomodulatory ipilimumab in a novel mock clinical trial, we hope to demonstrate that susceptible tumor subtypes can be identified by characterizing the genetic lesions and infiltrating cell populations which define a tumor. The product of these investigations will be a deeper understanding of genetic elements of the immune system influencing tumor susceptibility, as well as preliminary characterization of genetically defined tumor types likely t respond to immunomodulatory therapy.

Public Health Relevance

Immunomodulatory agents represent a novel class of anticancer therapeutics with extraordinary potential balanced by unpredictability and significant side effects. By comprehensively profiling tumors with differential interactions with the immune system in a mouse model it may be possible to characterize the genetic and immunological factors that define a responsive lesion. Using this information we may be able to improve our targeting with immunomodulatory agents, improving patient response and reducing the incidence of unnecessary side effects experienced by patients unlikely to respond.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F09B-P (20))
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Schmidt, Michael K
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Halliwill, Kyle D; Quigley, David A; Kang, Hio Chung et al. (2016) Panx3 links body mass index and tumorigenesis in a genetically heterogeneous mouse model of carcinogen-induced cancer. Genome Med 8:83
Westcott, Peter M K; Halliwill, Kyle D; To, Minh D et al. (2015) The mutational landscapes of genetic and chemical models of Kras-driven lung cancer. Nature 517:489-92