Our Preliminary Studies show that a single high dose of radiation or high doses of hypofractionated radiation administered to colon or breast tumors in mice can induce complete remissions as well as systemic anti-tumor immunity that is transferable with T cells. The T cells are required for tumor remissions. The goals of the current proposal are to determine the subsets of T cells in the spleen and lymph nodes that mediate anti-tumor immunity after transfer, and to determine whether T cells in tumors are immunodeficient and unable to transfer anti-tumor activity, and whether immune suppressor cells in the tumor can interfere with the transfer. In addition, we will determine the molecular basis of T cell migration to the tumors after radiotherapy by investigating chemokines produced by the tumors and chemokine receptors on the T cells that can infiltrate tumors. Finally, we will determine whether human pancreas tumors growing in immunodeficient mice can be induced to regress by radiation in the presence or absence of injected T cells from the tumor bearing patients. The proposed experiments use staining and flow cytometry to identify and purify immune cells for transfer studies and for analysis of tumor infiltrating cells. Gene modified mice are used to elucidate the key effector molecules used by anti-tumor T cells to mediate remissions and to traffic to tumors. The proposed studies are designed to be models for future clinical protocols that can use stereotactic body radiation (SBRT) in combination with chemotherapy and autologous T cell therapy to enhance the potency of current combinations of radiotherapy and chemotherapy to treat cancer.
Our Preliminary Studies showed that a single high of radiation to colon or breast tumors in mice can induce complete remissions as well as systemic anti-tumor immunity that is transferable with immune cells called T cells. The T cells are required for remissions. The proposed studies will determine the types of T cells that induce remissions, whether tumors contain cells that can suppress the transfer of anti-tumor activity, and whether human pancreas cancers growing in mice can be induced to regress in the presence or absence of injected T cells from the cancer patients.
|Brown, J Martin; Recht, Lawrence; Strober, Samuel (2017) The Promise of Targeting Macrophages in Cancer Therapy. Clin Cancer Res 23:3241-3250|
|Bhattacharya, Nupur; Yuan, Robert; Prestwood, Tyler R et al. (2016) Normalizing Microbiota-Induced Retinoic Acid Deficiency Stimulates Protective CD8(+) T Cell-Mediated Immunity in Colorectal Cancer. Immunity 45:641-655|
|Filatenkov, Alexander; Baker, Jeanette; Strober, Samuel (2016) Disruption of evasive immune cell microenvironment in tumors reflects immunity induced by radiation therapy. Oncoimmunology 5:e1072673|
|Segal, Ehud; Prestwood, Tyler R; van der Linden, Wouter A et al. (2015) Detection of intestinal cancer by local, topical application of a quenched fluorescence probe for cysteine cathepsins. Chem Biol 22:148-58|
|Filatenkov, Alexander; Baker, Jeanette; Mueller, Antonia M S et al. (2015) Ablative Tumor Radiation Can Change the Tumor Immune Cell Microenvironment to Induce Durable Complete Remissions. Clin Cancer Res 21:3727-39|
|Spitzer, Matthew H; Gherardini, Pier Federico; Fragiadakis, Gabriela K et al. (2015) IMMUNOLOGY. An interactive reference framework for modeling a dynamic immune system. Science 349:1259425|
|Filatenkov, Alexander; Baker, Jeanette; Müller, Antonia M et al. (2014) Treatment of 4T1 metastatic breast cancer with combined hypofractionated irradiation and autologous T-cell infusion. Radiat Res 182:163-9|
|Parker, Jennifer J; Jones, Jennifer C; Strober, Samuel et al. (2013) Characterization of direct radiation-induced immune function and molecular signaling changes in an antigen presenting cell line. Clin Immunol 148:44-55|