Tumorigenesis is controlled by mechanisms of immune surveillance. Natural killer cells are important mediators of innate anti-tumor immunity, and immunostimulatory dendritic cells and cytotoxic T cells participate in tumor suppression as well. However, physiologic mechanisms of effector cell recruitment for immune surveillance remain poorly understood. The underlying hypothesis of this proposal is that chemerin, a recently described chemoattractant for natural killer (NK) cells and subsets of dendritic cells, isa key physiological mediator of immune surveillance and of tumor immunity. This hypothesis is suggested by the observation that chemerin is downregulated at the gene level during tumorigenesis in animal models and in many human solid tissue neoplasms, including melanoma and prostate cancer.
Our Aims are as follows: 1: Determine whether tumor-expressed or intratumoral chemerin inhibits the establishment or growth of transplanted tumors, and define the role of the chemerin receptor CMKLR1 in chemerin-mediated tumor suppression. Well-established mouse models of transplantable tumors will be used. The effects of tumor- expressed or associated chemerin will be evaluated by comparing the in vivo and in vitro growth of tumor cells transfected with chemerin-encoding or control vectors, or of tumors injected with chemerin intratumorally. CMKLR1-deficient mice will be used to define the CMKRL1 in observed tumor suppression. Contralateral administration of wild type tumors or intravenous """"""""metastasis"""""""" models will assess the ability of local tumor chemerin expression to induce systemic anti-tumor immune responses. 2: Define cell types recruited to tumors by chemerin, and their involvement in chemerin suppression of tumor growth. The effects of chemerin on recruitment of tumor infiltrating leukocyte (TIL) subsets including NK cells, dendritic cells (DC), and lymphocytes will be studied by comparing TIL isolated from chemerin-expressing vs control tumors. To define their involvement in chemerin-mediated tumor growth inhibition, recruited leukocyte subsets will be depleted using antibody and genetic approaches. The role of CMKLR1 in recruitment of TIL subsets will be evaluated using CMKLR1-/- mice. 3. Test the hypothesis that endogenous chemerin mediates physiologic immune surveillance and inhibition of transformed cells during spontaneous tumorigenesis. The role of endogenous CMKLR1 and chemerin in tumor suppression will be evaluated in oncogene driven models of adenocarcinoma and melanoma development and metastasis. Tumor development, progression and differentiation will be compared in wild type, CMKLR1-/- and chemerin-deficient mice, and in mice engineered to have immune-cell specific CMKRL1 deficiency. The proposed studies will define the role of chemerin in the physiologic control of tumorigenesis, and will elucidate key mechanisms involved. The results may lead to novel approaches to engage host immune defenses for cancer therapy.
Cancer is a major health problem, and many cancers remain difficult or impossible to treat. Cancer develops initially as a single transformed or malignant cel. In order to survive and grow, the cell and its early offspring must escape the body's normal immune defense, mechanisms of immune surveillance that are thought to stop most transformed cells from becoming tumors. Our project studies a chemoattractant molecule that can attract natural killer and other immune cells that have been implicated in anti-tumor defenses. This chemoattractant is normally expressed in most tissues of the body, but is down-regulated in tumors leading us to hypothesize that tumors suppress it to avoid immune attack. We will test this hypothesis in mouse models of melanoma and prostate cancer. If we are correct, it may be possible to target this anti-tumor chemoattractant to cancers, or to induce it expression, as a new approach to cancer therapy.
|Pachynski, Russell K; Scholz, Alexander; Monnier, Justin et al. (2015) Evaluation of Tumor-infiltrating Leukocyte Subsets in a Subcutaneous Tumor Model. J Vis Exp :|
|Zabel, Brian A; Rott, Alena; Butcher, Eugene C (2015) Leukocyte chemoattractant receptors in human disease pathogenesis. Annu Rev Pathol 10:51-81|
|Graham, Kareem L; Zhang, Jian V; LewÃ©n, Susanna et al. (2014) A novel CMKLR1 small molecule antagonist suppresses CNS autoimmune inflammatory disease. PLoS One 9:e112925|
|Lahl, Katharina; Sweere, Johanna; Pan, Junliang et al. (2014) Orphan chemoattractant receptor GPR15 mediates dendritic epidermal T-cell recruitment to the skin. Eur J Immunol 44:2577-81|
|Oderup, Cecilia; LaJevic, Melissa; Butcher, Eugene C (2013) Canonical and noncanonical Wnt proteins program dendritic cell responses for tolerance. J Immunol 190:6126-34|