Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Even with aggressive surgical resection, radiation and chemotherapy, GBM patients only have an average median survival of 14.6 months post-diagnosis. One hallmark of GBM tumors is the accumulation of infiltrating regulatory T cells (Tregs), a highly immunosuppressive T cell subset that suppresses immune-mediated GBM rejection. Thus, one of the barriers to durable GBM immunotherapy is the recruitment of Tregs to the tumor microenvironment. Previous work has demonstrated that the Treg-recruiting chemokine, CCL22, is expressed in patient-resected GBM tissue. Importantly, the number of Tregs expressing CCR4, the cognate chemokine receptor for CCL22, is increased in the peripheral blood of GBM patients. While this indirect association suggests that the CCL22-CCR4 interaction is critical for Treg homing, no previous study has investigated the physiological relevance of this interaction. We therefore hypothesize that, CCL22-expressing GBM cells recruit CCR4+ Tregs leading to increased Treg levels, a suppression of T cell-mediated tumor rejection and overall decreased survival. To test this hypothesis, we propose: 1) to determine the impact of tumor- derived CCL22 on Treg recruitment, 2) to determine the role of CCR4 in Treg homing to GBM, and 3) to investigate the therapeutic efficacy of a CCR4 antagonist in the stabilization of anti-tumor immunity analyzed in pre-clinical orthotopic and transgenic mouse models of GBM. The proposed studies aim to investigate translationally relevant approaches that reverse immunosuppression in GBM, which is a critical first step to the rational design of effective immunotherapy for patients with incurable brain cancer.
Glioblastoma multiforme (GBM) is an incurable form of brain cancer with an extremely poor prognosis: average patient survival post-diagnosis is 14.6 months. In GBM, regulatory T cells (Tregs) accumulate at high levels within the tumor and promote immunosuppression, representing a significant barrier to immunotherapy approaches. Recent work in vitro has implicated an exciting potential role for CCR4-CCL22 signaling in Treg trafficking to GBM. This project aims to establish CCR4-CCL22 signaling for Treg recruitment to GBM through in vivo models and determine whether pharmacological inhibition of CCR4 can enhance anti-tumor immunity. This is relevant to the NIH mission in that fundamental knowledge of cancer immunobiology will be applied to the design of therapeutic strategies to reduce the burden of cancer on human health.
|Chang, Alan L; Miska, Jason; Wainwright, Derek A et al. (2016) CCL2 Produced by the Glioma Microenvironment Is Essential for the Recruitment of Regulatory T Cells and Myeloid-Derived Suppressor Cells. Cancer Res 76:5671-5682|