Abstract IA4: T cell subsets in the tumor microenvironment.

Our research interests are in tumor immunopathology and immunotherapy, with an emphasis on the cross-talk among immune cell subsets (Treg cells, Th17 cells, effector CD8+ T cells and APCs), tumor cells and tumor stem cells in the tumor microenvironment, and its impact on tumor immunity, tolerance and therapy. Over the past few years, we have achieved important insights into cancer immunopathogenesis in patient with cancer. Our prior research efforts demonstrate that the tumor microenvironment is comprised of immune cells that have been reprogrammed by active tumor-mediated processes to defeat tumor-specific immunity and promote tumor growth in a highly effective manner. These studies have helped define the nature of immune responses in the tumor microenvironment, and provide significant new insights into designing novel immune therapies to target the immune suppressive mechanisms including Treg cells (1-6), inhibitory B7 family members (7-10) and Galectin-9/Tim3 signaling (11) to treat patients with cancer (12, 13). In this talk I focus on two T cell subsets in the tumor microenvironment, Th17 (14-18) and Tregs(1-6). In the first part of my talk, I will briefly review the stem cell-like feature of Th17 cells in human cancer. Th17 cells phenotypically resemble to terminally differentiated memory T cells, but are different from central memory, exhausted and senescent T cells. Despite their phenotypic markers of terminal differentiation, Th17 cells have stem cell-like features including high capacity of proliferative self-renewal, potent persistence and apoptotic resistance in vivo, and the generation of other types of T helper cells. These features are controlled by the signaling pathways of hypoxia inducible factor (HIF)1α, Notch and Bcl2. Targeting Th17 stemness would be therapeutically meaningful for treating patients with chronic diseases affected by Th17 cells (19). In the second part of my talk, I will discuss Tregs in the tumor bone marrow microenvironment (20, 21). Bone marrow is a predetermined metastatic location for multiple human tumors including breast cancer and prostate cancer. Bone marrow Tregs may define the cellular and molecular predilection for cancer to metastasize to bone marrow. High levels of functional Tregs are found in the bone marrow microenvironment in prostate cancer patients with bone metastasis. CXCR4/CXCL12 signaling pathway contributes to Treg bone marrow trafficking. Tregs exhibit active cell cycling in the bone marrow, and bone marrow dendritic cells express high levels of receptor activator of NF-kB (RANK), and promote Treg expansion through RANK and its ligand (RANKL) signals. Furthermore, Tregs suppress osteoclast differentiation induced by activated T cells and M-CSF, adoptive transferred Tregs migrate to bone marrow, and increase bone mineral intensity in the xenograft mouse models with human prostate cancer bone marrow inoculation. In vivo Treg depletion results in reduced bone density in tumor bearing mice. The data indicates that bone marrow Tregs may form an immunosuppressive niche to facilitate cancer bone metastasis and contribute to bone deposition, the major bone pathology in prostate cancer patients with bone metastasis. These findings mechanistically explain why Tregs accumulate in the bone marrow, and demonstrate a previously unappreciated role for Tregs in patients with prostate cancer. Thus, targeting Tregs may not only improve anti-tumor immunity, but also ameliorate bone pathology in prostate cancer patients with bone metastasis. Citation Format: Ilona Kryczek, Weiping Zou. T cell subsets in the tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr IA4.