There are currently no comprehensive or satisfactory explanations for how tumors evade the immune response. Much of our knowledge about tumor immunoevasion is limited to individual mechanisms that have been therapeutically targeted with single drugs. However, tumors evolve multiple, redundant strategies to circumvent immune surveillance. This plasticity has contributed to the modest efficacy of cancer immunotherapies that only target one/several pathway(s). The challenge we face is: to comprehensively decipher the mechanisms tumors use to evade immune surveillance. Specifically, how can we determine which of these may be redundant and which may be ideal drug targets (e.g., non-redundant mechanisms)? Similarly, which pathways crucial for tumor immunoevasion might synergize and require several drugs to achieve effective immunotherapy? In order to address this challenge we will establish assays that intentionally select for mutations that allow a tumor to escape an immune response. Using the power of immunologic selective pressure, we will indentify mechanisms that work alone and in combination to allow a tumor to escape immunity. Our central hypothesis is that tumors evolve immunosuppressive gene expression patterns specific to their microenvironment to evade immune attack. We further hypothesize that those changes in gene expression can be rapidly indentified by functional genomics approaches. We have previously used transposon-based mutagenesis to indentify mutations that initiate tumors. Transposons are mobile genetic elements that can be designed to cause mutations that are rapidly identifiable. Herein we will customize transposon-based mutagenesis to identify genes that allow a tumor to thrive despite the presence of high numbers of tumoricidal T cells.
Our specific aim i s to identify and validate genes that promote escape from immune surveillance in gliomas, an aggressive form of brain cancer. To accomplish this, mutagenic transposons will be mobilized in cultured glioma cells. Mutagenized glioma cells will be implanted into mice with pre-established immunological memory to select for tumor cells that only grow when immune evasion is achieved. In parallel, we will carry out a similar genetic screen in mice with spontaneously arising gliomas that are treated by infusion of tumor-specific T cells. Transposon insertions will be cloned, sequenced and statistically analyzed to identify genes that are repetitively mutated in many tumors that escape immunity. Candidate genes will be functionally validated in tissue culture and animal model experiments to establish cause and affect relationships between their expression and immunoevasion. IMPACT: The identification of integrated pathways that tumors require to escape immune responses in order to thrive, which will ultimately lead to the development of drugs that increase the efficacy of cancer immunotherapy.
Tumors are continuously eliminated in our bodies by a process called immunosurveillance. When immunosurveillance fails, clinically apparent tumors arise that cause significant morbidity and mortality. Therefore, discovery of the processes that allow a tumor to escape the immune response is vital to improve the effectiveness of immune-based treatments for cancer. Herein we will establish assays that allow for the rapid identification of novel mechanisms by which tumors escape the immune response. Several of these immune escape mechanisms will be validated as potential targets for future drug development. The ultimate impact of these studies will be the development of more effective immune-based therapies for the treatment of cancer.
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|Litterman, Adam J; Dudek, Arkadiusz Z; Largaespada, David A (2013) Alkylating chemotherapy may exert a uniquely deleterious effect upon neo-antigen-targeting anticancer vaccination. Oncoimmunology 2:e26294|
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|Murphy, Katherine A; Lechner, Melissa G; Popescu, Flavia E et al. (2012) An in vivo immunotherapy screen of costimulatory molecules identifies Fc-OX40L as a potent reagent for the treatment of established murine gliomas. Clin Cancer Res 18:4657-68|
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