Targeting Regulatory B Cells to Augment Anti-Bladder Cancer Immunity
Abstract
Objective and Rationale: My overall objective for the proposed research is to identify novel methods to target a bladder cancer (BC) patient’s immune system in order to improve survival in BC patients. Despite recent advances in treatment for patients with metastatic BC, only a subset of patients experience significant tumor shrinkage with these therapies. Thus, most BC tumors develop resistance to approved therapies, and overall survival in patients who have had metastatic BC for 5 years is ~6%. Bladder cancer tumors hijack the immune system to promote tumor growth. Thus, there is an urgent need to better understand how this happens in order to develop therapies that can reprogram the immune system to promote antitumor immune attack. My ultimate goal is to develop novel immune-based therapies in order to improve outcomes for patients with advanced BC. My preliminary data suggest that an immune cell called a B cell facilitates tumor growth in a clinically relevant mouse model of BC. I hypothesize this is because a subset of B cells inhibits the ability of other immune cells to kill tumors. B cells are a heterogeneous group of immune cells that can stimulate the immune system to promote tumor clearance, or suppress immunity to promote tumor growth. We have found that in patients with advanced BC who subsequently received approved immunotherapy, a subset of patients with increased tumor expression of a B cell gene signature (suggesting more B cells are present) have worse response to immunotherapy. This implicates a subset of B cells drive resistance to immunotherapy. The rationale for these experiments is that defining how immune suppressive B cells block antitumor immune activation is likely to reveal targets for therapeutic intervention in these patients. After identifying the proteins expressed by immune suppressive B cells in patients with advanced BC, I plan to target these proteins in clinical trials, which may improve survival in these patients. Career Goals: My long-term career goal is to be an internationally recognized laboratory based BC physician-scientist whose work transforms survival for BC patients by determining how B cells block immune mediated BC eradication. By completing the proposed experiments, I expect to identify novel B cell based mechanisms that facilitate BC growth, and can be targeted in patients with advanced BC to improve their survival (PRCRP Overarching Challenge: Transform cancer treatment through the identification of new targets). My career development plan utilizes a multidisciplinary research committee committed to aggressive mentoring in basic BC biology, bioinformatics, statistics, the analysis of B cells in humans and mice, and the development of an independent research program. I will benefit from access to unique BC samples and numerous core facilities, a rich collaborative environment of clinicians and scientists, and educational seminars and coursework. By completing the proposed experiments and career development activities, I expect to identify B cell targets to transition to BC clinical trials. Applicability and Timeline: I expect this research to improve survival of patients with BC by developing therapies to target immune-based mechanisms (discovered as a part of the proposed research) that facilitate BC growth. To the best of my knowledge, this will be the first comprehensive examination of the B cell landscape in patients with BC. As little research has been performed to define the role of B cells in BC, I estimate that it will take 2-3 years to identify the most promising B cell specific targets to pursue in clinical trials. This will be followed by early clinical studies, which typically take 2-4 years to demonstrate whether the tested treatment results in significant improvement in clinical outcome. Impact of Research on the Military Population: The proposed experiments will improve outcomes for current and retired military personnel and th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310317
Entities
People
- Burles Johnson
Organizations
- Johns Hopkins University
- United States Army