Conversion and expansion of FOXP3+ Treg in tumor microenvironment Recent clinic and animal studies have provided compelling evidence for the dominant role of forkhead- box transcription factor Foxp3-expressing regulatory T cells (Foxp3+ Tregs) in suppressing antitumor immune responses. Foxp3+ Tregs are found to be elevated during the pathogenesis of diverse solid tumors and hematopoietic malignancies, and more importantly, expansion and accumulation of Foxp3+ Tregs at the tumor site is associated with advanced tumor growth and poor survival prognosis. However, it remains elusive where the tumor-associated Foxp3+ Tregs come from, and how and why they accumulate preferentially inside tumor lesions. The overall goal of our research is to understand the origin and molecular nature of tumor-associated Foxp3+ Tregs, and their regulation and mechanisms of action that contribute to poor immunogenicity and immune evasion of malignant tumors. In this proposal we will focus our study on tumor-induced de novo generation of Foxp3+ Tregs. Our central hypothesis is that growing tumor creates a microenvironment conducive to convert tumor antigen-reactive nonregulatory precursor cells into suppressive Foxp3-expressing Tregs. We will take two complementary approaches to test this hypothesis by determining: (1) the potential of na?ve CD4+ TCR transgenic T cells to undergo tumor antigen-induced conversion to Foxp3+Treg cells inside tumor tissue; (2) the actual contribution of de novo induction of Foxp3+ Treg cells from normal wildtype CD4+ precursors to the total pool of tumor-infiltrating Foxp3+ Treg cells. Understanding these basic parameters is of critical importance to devise novel therapeutic paradigms that aim at boosting spontaneous and vaccine-induced immune responses against malignant cells through manipulating the presence and/or activity of Tregs specifically at the tumor site. Furthermore, in addition to cancer, the approaches and systems (in particular, the GFP reporter mice) developed here could also be applied to study the behavior of Foxp3+ regulatory T cells in other disease settings, including chronic infection, allergy, autoimmunity and transplant rejection. ? ? ?
| Kastner, Lauren; Dwyer, David; Qin, F Xiao-Feng (2010) Synergistic effect of IL-6 and IL-4 in driving fate revision of natural Foxp3+ regulatory T cells. J Immunol 185:5778-86 |
| Wei, Jun; Duramad, Omar; Perng, Olivia A et al. (2007) Antagonistic nature of T helper 1/2 developmental programs in opposing peripheral induction of Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A 104:18169-74 |
