Regulatory T cells (Treg) are the master immune-suppressor cells, with a double-edged sword. Treg protect us from autoimmunity, damages from excessive inflammation, and help us maintaining homeostasis in mucosal surface. On the other hand, Treg can be negative force against anti-tumor immunity in the tumor microenvironment (TME), which need to be targeted to maximize the effects of cancer immunotherapies. However, the exact phenotype and molecular basis of suppressive function of Treg in the TME have not been fully elucidated. Especially of translational relevance; what is the phenotype of tumor-infiltrating Treg (TIL-Treg) under the fundamental cancer therapy such as radiotherapy, and what is the determinant molecules for human TIL-Treg have not been fully elucidated.
To answer those questions, in my thesis projects, I have elucidated the TIL-Treg phenotype post radiotherapy (RT), and discovered novel human TIL-Treg targeting molecules.
In RT-Treg project, we have shown that RT significantly increased the phenotypically activated and, importantly functionally suppressive Treg in the TME. To the best of our knowledge, we were the first to demonstrate that irradiated TIL-Treg are indeed functionally suppressive, using the in vitro micro-suppression assay, using TIL post-RT. Our results also suggest that post-RT Treg expansion is likely independent of TGF-beta nor IL-33, but at least partly due to the proliferation of the Treg in the tumor.
In human TIL-Treg project, we performed RNAseq from prostate cancer, glioblastoma and renal cell carcinoma (and urothelial carcinoma as well) patients and identified novel targets highly expressed in TIL-Treg, including DUSP1, DUSP4, RGS1 (and RGS16). Despite its high expression in Treg, DUSP1 showed unique downregulation upon activation, which presents a stark contrast with most Treg-associated molecules many of which increase their expression in activation. DUSP1 accordingly showed reciprocal expression pattern with DUSP4. From the data and close homology with DUSP1 and DUSP4, I hypothesized that DUSP1 and DUSP4 reciprocally regulate Treg activation and function. In depth in vitro and in vivo studies are underway to further elucidate the functional roles of these molecules in TIL-Treg (and TIL)
