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Improvement of cellular immunotherapy during dysbiosis- Resubmission

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Summary/Abstract The use of antibiotics has significantly increased in recent years. Antibiotics (ABX) severely alter the gut microbiome, destroying potentially pathogenic bacteria, as well as beneficial ones?producing a state of microbial imbalance called dysbiosis. Notably, a diminished gut microbiome has severe defects on the immune system, yet how these defects may affect cellular immunotherapy is largely unknown. To better understand how dysbiosis influences cellular immunotherapy, we focused on melanoma as an exemplary immunogenic solid tumor. The incidence of melanoma has increased drastically over the past decades, with its morbidity rate continuing to outpace that of most other cancers. Early stages of melanoma are often successfully controlled and treated; yet patients with advanced stages of melanoma are treated with cellular immunotherapy and only 50% respond. We hypothesize that ABX-induced dysbiosis dictates, at least in part, the reduction in treatment efficacy. Our overall goal is to define the systemic effects of antibiotic-induced dysbiosis on the distal tumor microenvironment and develop therapies to promote antitumor immunity. The major objective of this application is to overcome dysbiosis-induced ICAM-1 suppression and thereby enhance the effectiveness of cellular immunotherapy. Attaining this objective will be the next step in increasing the efficacy and response rate of immunotherapies. We formulated a robust and unbiased approach using various melanoma models to accomplish the following Aims: Aim 1. Identify ABX primarily responsible for stromal immune suppression resulting in tumor progression. Aim 2. Increase ICAM-1 on tumor-associated endothelial cells during dysbiosis. Aim 3. Increase cellular immunotherapy efficacy in melanoma during dysbiosis. Completing these aims will expand our understanding on how antibiotics-induced perturbation of the gut microbiome impacts the distal tumor microenvironment. This work has the potential to establish new paradigms aimed at enhancing the efficacy and response rate of immunotherapies by modulating the tumor vasculature, as all types of immunotherapy ultimately dependent on efficient trafficking of effector leukocytes into the tumor.

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