ABSTRACT There are an estimated 765,000 people with a diagnosis of bladder cancer living in the United States and risk of disease recurrence and progression can be high. Frequent, invasive transurethral screening procedures to monitor for recurrence and progression burden both patients and the health care system. A better understanding of the tumor-associated immune responses in bladder cancer patients could provide for more informed clinical decisions on the necessary frequency of invasive follow up procedures and reduce patient morbidity. We propose to leverage an existing population-based study of bladder cancer that includes a range of patient age groups, has several years of follow up, includes patient treatment and outcome data, as well as matched tumor samples. Our collaborative group has developed and extensively validated epigenetic biomarkers of leukocyte subtypes allowing the use of archival DNA to study immune profiles. Here we will use our proven framework to expand our repertoire of leukocyte epigenetic biomarkers to include myeloid derived suppressor cells (MDSC), and test and validate the relation of MDSC and other leukocyte subtypes (including the neutrophil to lymphocyte ratio: NLR), and cell type activation states with bladder cancer outcomes; recurrence, progression, and survival. We will use time-to-event analysis and aim to understand the independent contributions of immune profiles, age at diagnosis, tumor stage and grade, smoking history, and treatment (including BCG immunotherapy), with bladder cancer outcomes. In addition, we propose to measure somatic alteration profiles of bladder tumors from matched subjects and assess the relation of blood immune signatures with tumor methylation and survival to understand the crosstalk between tumor profiles and patient immune responses. Finally, in an exploratory aim we will prospectively investigate both pre-treatment and post- treatment immune signatures in bladder cancer patients. At this opportune time of emerging immunomodulatory therapeutics our existing population-based study resource provides a cost-efficient setting to advance towards improved risk projection in newly diagnosed patients by ushering in a novel and flexible immune monitoring toolkit that can inform clinical decision-making using data on tumor-associated immune responses.