Targeting regulatory T cells in experimental colon cancer with radioimmunotherapy
Date
2024-01-05
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
Type
Thesis
Degree Level
Masters
Abstract
Colorectal cancer remains a formidable threat to human health around the world and has become the third most common cancer worldwide. However, over the past 20 years, there has been a lack of breakthroughs in the treatment of colorectal cancer, especially for advanced colorectal cancer. Only a limited number of treatment options are available, and treatment outcomes significantly vary. Immunotherapy with immune checkpoint inhibitors while becoming a game changer for various types of cancer, produces mixed results in colorectal cancer with only a small number of patients experiencing long term progression-free survival. Regulatory T cells (Tregs) are an immunosuppressive subset of T lymphocytes, and a particular subset of Tregs, so called tumor infiltrating Tregs (ti-Tregs) can interfere with immunotherapy mechanism of action resulting in decreased efficacy. In recent studies, CCR8, or C-C motif chemokine receptor 8, has emerged as a highly expressed cell surface protein found exclusively in tumor-infiltrating Tregs, including those in colorectal cancer tumors. This makes CCR8 a promising target for radioimmunotherapy (RIT) to selectively eliminate ti-Treg cells. RIT allows for precise delivery of highly cytotoxic radionuclides to localized or systemic cancer deposits. In this study, we tested the hypothesis that using CCR8 as a target in RIT could eliminate ti-Tregs within colorectal tumors, potentially enhancing the success of subsequent immunotherapy. We validated the ability of our antibodies to bind to ti-Tregs in colorectal cancer tumors in mouse tumor models by microSPECT/CT imaging and confirmed a reduction in ti-Treg cells post-RIT with 225Actinium-labeled anti-CCR8 antibody within the experimental group's tumor samples through immunohistochemistry (IHC) analysis. Subsequent combination therapy experiments with 225Actinium-labeled anti-CCR8 antibody and anti-CTLA4 immunotherapy established the feasibility of the combination therapy in mouse colorectal cancer models, revealing a synergistic effect of the RIT and immunotherapy combination. The results of these combination therapy experiments suggest a more effective strategy for colorectal cancer treatment which can also be a viable approach for various other cancer types. In other words, choosing CCR8 as a treatment target for RIT to enhance the success of subsequent immunotherapy holds significant promise, regardless of the specific cancer type, if high CCR8 expression ti-Tregs exists within the tumor microenvironment.
Description
Keywords
Colorectal cancer, Radioimmunotherapy, Regulatory T cells
Citation
Degree
Master of Science (M.Sc.)
Department
Pharmacy and Nutrition
Program
Pharmacy