Mechanisms Of Oncolytic Orf Virus-Induced Anti-Tumor Immunity
Cancer immunotherapies are slowly becoming accepted into mainstream oncology based on the promise of inducing durable anti-tumor immune responses to improve patient outcomes. Rapid advances have been seen in the pre-clinical development and clinical evaluation of oncolytic virus (OV)-based therapies, which have emerged as promising treatment modalities. Recently, OVs have been appreciated as much more than cytolytic agents to tumors, in their ability to remodel the tumor microenvironment (TME) and reverse pro-malignant, immune- suppressive milieus. A key component to the clinical success of OVs is the ability to generate inflammation in the TME, promote immune infiltration and drive tumor-directed immune responses. Thus, detailed studies of immune cell phenotypes and functions within the TME following OV therapy is crucial in identifying determinants that are fundamental or detrimental to therapeutic success, and in deciphering mechanisms of response as well as resistance in patients. In this thesis, a method for evaluating the antibody response to tumors and viral-based therapies is described, which researchers can use to expand their analyses of immunotherapies. The final two research chapters evaluate the mechanisms behind the anti-tumor efficacy elicited by the oncolytic poxvirus, Parapoxvirus ovis (Orf virus, OrfV) in two challenging models of late-stage ovarian cancer and melanoma lung metastases. In both models, OrfV promoted the infiltration of immune effector cells with increased expression of markers and cytokines associated with activation and anti-tumor function into the TME. Frequently underappreciated components of the immune response emerged as contributors to OrfV-induced anti-tumor immunity, emphasizing the importance of dissecting the interaction between OVs and immune cells within the TME. The immune-stimulating potential of OrfV directly correlated with improved disease outcomes, and insight gained from immune-monitoring proved effective for informing treatment approaches to enhance efficacy. The work in this thesis provides an additional tool for researchers to detect anti-cancer immune responses, expands our knowledge of the influence OVs can have on the immune system, and provides researchers with a better understanding of the previously underappreciated roles that cells of the innate and adaptive systems may play in tumorigenesis, anti-viral and anti-tumor immunity.
Minott JA, Van Vloten JP, Yates JG, Chan L, Wood G, Viloria-Petit A, Karimi K, Petrik JJ, Wootton S & Bridle BW. Multiplex Flow Cytometry-Based Assay for Quantifying Tumor-and Virus-Associated Antibodies Induced by Immunotherapies. Frontiers in Immunology, 6874.