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A vast majority of human tumors express interferon-stimulated genes (ISGs), indicating that the activation of pathways controlling the induction of ISGs is a pervasive feature of cancer. Typically, ISGs result from pathogens, such as viruses, that are recognized by a class of receptors called pattern recognition receptors (PRRs). This leads to the induction of the anti-viral cytokine interferon (IFN). In the context of viral infection, this anti-viral response has many effects that include direct anti-pathogen function, regulation of innate and adaptive immune responses, and control of tissue regeneration. However, in the case of cancer, the engagement of PRRs and subsequent expression of ISGs is generally not due to virus infection but rather endogenous molecules in cancer cells and/or the tumor microenvironment that mimic viruses. A main focus of my research program is to understand: 1) the nature of the endogenous molecules in cancer cells or the tumor microenvironment that can mimic viruses, 2) why cancer cells evolve to recognize endogenous molecules as they would foreign pathogens, 3) what function this serves, and 4) the clinical/translational relevance of this "virus mimicry".
Emerging evidence indicates that in tumors, IFN and anti-viral signaling pathways can be activated by endogenous nucleic acids. This recognition of self RNA and/or DNA as foreign can occur during cancer progression or in response to cancer therapies. What ensues include a wide variety of different and often opposing effects on cancer cells and immune cells in the tumor. For example, one important consequence of IFN/PRR signaling in cancer is its impact on the immune system and on response to cancer immunotherapy. Activation of anti-viral pathways can engage the immune system against cancer to enhance efficacy of immune checkpoint blockade and chimeric antigen receptor (CAR) T cells. This is one rationale for combining conventional cancer therapies such as radiation and chemotherapy with immunotherapy. However, chronic PRR/IFN signaling can also have unwanted consequences. In particular, prolonged IFN signaling in the tumor that accompanies persistent disease can unexpectedly promote immunosuppression through IFN-mediated feedback inhibition. This inhibitory property of IFN signaling is a normal homeostatic function that is evident in chronic pathogen infections and serves to limit immune-mediated pathology. In cancer, tumors can co-opt this suppressive function of IFN signaling to render them particularly resistant to immunotherapy and to attack by adaptive and innate immune cells. Other unfavorable properties of IFN/PRR signaling in cancer include the promotion of tumor progression, metastasis, and even resistance to conventional cancer therapies.
To better understand the regulation, function, and significance of PRR/IFN signaling in cancer, cancer therapies, and immune regulation, we rely on multiple strategies. First, we utilize approaches that enable data-driven hypothesis generation using data acquired from biological systems that capture effects of cell-cell (particularly cancer and immune cell) interactions. This includes a reliance on in vivo and genome-based methods. Second, to understand disease-relevant biology, we prioritize perturbation effects that appear shared between mouse models and human cancer. Ultimately, our objective is to translate findings from bench to bedside by working with colleagues to inform the design of clinical trials.
A vast majority of human tumors express interferon-stimulated genes (ISGs), indicating that the activation of pathways controlling the induction of ISGs is a pervasive feature of cancer. Typically, ISGs result from pathogens, such as viruses, that are recognized by a class of receptors called pattern recognition receptors (PRRs). This leads to the induction of the anti-viral cytokine interferon (IFN). In the context of viral infection, this anti-viral response has many effects that include direct anti-pathogen function, regulation of innate and adaptive immune responses, and control of tissue regeneration. However, in the case of cancer, the engagement of PRRs and subsequent expression of ISGs is generally not due to virus infection but rather endogenous molecules in cancer cells and/or the tumor microenvironment that mimic viruses. A main focus of my research program is to understand: 1) the nature of the endogenous molecules in cancer cells or the tumor microenvironment that can mimic viruses, 2) why cancer cells evolve to recognize endogenous molecules as they would foreign pathogens, 3) what function this serves, and 4) the clinical/translational relevance of this "virus mimicry".
Emerging evidence indicates that in tumors, IFN and anti-viral signaling pathways can be activated by endogenous nucleic acids. This recognition of self RNA and/or DNA as foreign can occur during cancer progression or in response to cancer therapies. What ensues include a wide variety of different and often opposing effects on cancer cells and immune cells in the tumor. For example, one important consequence of IFN/PRR signaling in cancer is its impact on the immune system and on response to cancer immunotherapy. Activation of anti-viral pathways can engage the immune system against cancer to enhance efficacy of immune checkpoint blockade and chimeric antigen receptor (CAR) T cells. This is one rationale for combining conventional cancer therapies such as radiation and chemotherapy with immunotherapy. However, chronic PRR/IFN signaling can also have unwanted consequences. In particular, prolonged IFN signaling in the tumor that accompanies persistent disease can unexpectedly promote immunosuppression through IFN-mediated feedback inhibition. This inhibitory property of IFN signaling is a normal homeostatic function that is evident in chronic pathogen infections and serves to limit immune-mediated pathology. In cancer, tumors can co-opt this suppressive function of IFN signaling to render them particularly resistant to immunotherapy and to attack by adaptive and innate immune cells. Other unfavorable properties of IFN/PRR signaling in cancer include the promotion of tumor progression, metastasis, and even resistance to conventional cancer therapies.
To better understand the regulation, function, and significance of PRR/IFN signaling in cancer, cancer therapies, and immune regulation, we rely on multiple strategies. First, we utilize approaches that enable data-driven hypothesis generation using data acquired from biological systems that capture effects of cell-cell (particularly cancer and immune cell) interactions. This includes a reliance on in vivo and genome-based methods. Second, to understand disease-relevant biology, we prioritize perturbation effects that appear shared between mouse models and human cancer. Ultimately, our objective is to translate findings from bench to bedside by working with colleagues to inform the design of clinical trials.
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