Identification of specific tumor antigens recognized by cytotoxic T cells has greatly accelerated efforts todevelop effective immunotherapies for cancer, but this knowledge has not yielded clinically effectivestrategies. The major impediments have been a subset of CD4+ regulatory T (Treg) cells that can negativelyregulate effector T cells, thus diminishing their antitumor effects. Thus, the long-term goals of Project 4 areto develop and test in a clinical setting new strategies that will reverse the suppressive effects of Treg cells inpatients with follicular lymphoma (FL). This broad objective will be pursued in four specific research aimssuggested by the applicant's recent demonstration of high percentages of Treg cells in clinical samples of FLand a novel discovery that Toll-like receptors (TLRs) in Treg cells can be manipulated to reverse theirsuppressive function.
Aim 1 seeks to identify and define discrete subsets of Treg cells in FL samples, anddetermine their mechanism(s) of immune suppression.
Aim 2 will identify and characterize the naturalligands of antigen-specific FL-derived Treg cells to understand how such cells are activated and maintainedat tumor sites.
Aim 3 asks whether TLR signaling controls Treg cell suppressive function in follicularlymphoma as it does in melanoma and other tumors, and whether Poly-G nucleotides are indeed the optimalligands for manipulating Treg cell function. A Phase I clinical trial is planned to demonstrate the feasibility ofusing TLR ligands as drugs to reduce or reverse Treg cell suppressive function in patients with FL. Themajor strengths of this application are (1) the availability of established CD4+ CD25+ Treg cell lines derivedfrom different types of cancer including FL, (2) the development of all requisite technologies (some unique)needed to analyze Treg cell function and identify optimal TLR ligands, and (3) compelling preliminary data onthe reversal of Treg cell function through TLR signaling, A positive outcome for this translational researchproject would open new opportunities for removing a major impediment to effective immunotherapy forfollicular lymphoma and perhaps other types of tumors as well.Lay summary: Therapies designed to enhance the ability of a patient's immune system to attack cancer cellsare often thwarted by a small subset of the patient's immune cells called Treg cells. This application aims tofind ways to downregulate Treg cells so that the patient's immune system can effectively fight cancer.
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