One of the major impediments to effective immunotherapy for cancer has been the influence of negativemmunoregulatory mechanisms on otherwise potent immune responses, including CD4+ CD25+ negativeregulatoryT cells (Tregs) contained in the tumor-infiltrating lymphocyte population. Investigators in Project 2(R. Wang, Leader) recently shifted their research to this problem after finding that some of their newlydiscovered EBV-EBNA1-derived T-cell epitopes could stimulate both CD4+ effector and Treg cells, thelatter having the capacity to suppress na'i've T-cell proliferation and immune responses. Further work toexploit this observation showed that TLR8 ligands (Poly-G oligonucleotides) can directly reverse thesuppressive function of Treg cells. Consequently, Wang and his group have postulated that EBV-positiveHodgkin disease (HD) and nasopharyngeal carcinoma (NPC), tumors of wide interest to this programproject, are enriched with Treg cells whose suppressive function could inhibit the therapeutic effect of T-cellimmunotherapy. They will pursue this concept in the current proposal, using both in vitro and in vivo models.
In Aim 1 they intend to establish the subsets and prevalence of Treg cells in clinical tumor samples andblood from patients with HD or NPC and then elucidate their suppressive function and mechanisms in humantumor mouse models. To link TLR8 signaling to Treg suppressive function, they propose in Aim 2 to exploitRNA interference (RNAi)-mediated knockdown and TLR8 transgenic mice to determine the signalingpathways or, at least, the key molecules controlling Treg cell function. Ultimately, in Aim 3, they will testthree novel strategies in transgenic mice that may improve antitumor responses to cancer vaccines andCTL-based immunotherapy for EBV-positive tumors: 1) use of TLR8 ligands to block the suppressivefunction of Treg cells; 2) as in 1 except the ligands will be covalently linked to MHC class II- and l-restrictedpeptides/proteins to enhance CD4+ and CD8+ T-cell responses; and 3) a combination of 1 and 2. Theresults of this research will be of considerable interest to investigators in Projects 1, 3 and 4, as theavailability of a method to suppress Treg cell function in the tumor microenvironment would nicelycomplement efforts to render EBV-positive or negative tumor cells resistant to the direct inhibitory effects ofcytokines and other factors that can impede the antitumor activity of CTLs. Lay summary - Among themany obstacles to effective immunotherapy for cancer, the negative activity of T cells with the ability tosuppress immune responses has been the most difficult to overcome. This group of investigators hasidentified an agent that can eliminate this barrier in the laboratory and now propose to find the best way touse it to neutralize unwanted T cells in the body.
Showing the most recent 10 out of 217 publications
