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Modulation of indoleamine 2,3‐dioxygenase pathway by a combination therapy strategy targeting myeloid derived suppressor cell function in lung cancer
Author(s) -
Schafer Cara,
Jin Tong Huan,
Sawant Anandi,
Roth Justin,
Grant Stefan,
Ponnazhagan Selvarangan,
Deshane Jessy
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1105.25
Subject(s) - indoleamine 2,3 dioxygenase , immunosuppression , cancer research , myeloid derived suppressor cell , tumor microenvironment , combination therapy , lung cancer , medicine , immunology , immunotherapy , immune system , cancer , biology , pharmacology , oncology , suppressor , tryptophan , biochemistry , amino acid
Immunosuppression in the tumor microenvironment (TME) has dampened the efficacy of current front line combination chemotherapies for lung cancer thus providing limited improvement in patient survival. Myeloid Derived Suppressor Cells (MDSCs) are the major contributors of immunosuppression by producing Reactive Oxygen Species (ROS) and by modulating amino acid metabolism in the TME. Indoleamine 2,3‐dioxygenase (IDO) is an intracellular enzyme that is a key regulator of tryptophan metabolism and is involved in immunosuppression. We have previously shown that a combination strategy using gemcitabine, a front line therapy for lung cancer and inhibitor of MDSC expansion, along with a Superoxide Dismutase (SOD) mimetic, which targets ROS in the TME, enhanced anti‐tumor immunity in mice and prolonged survival compared to controls. We hypothesized that this combination therapy will modulate IDO expression and activity and will diminish tumor burden. By flow cytometry and Western blot analyses, we demonstrate a significant reduction in IDO + immunosuppressive cell types within tumor and in overall IDO expression in tumor and lung tissues, respectively, of tumor challenged mice treated with combination therapy compared to controls. Our preliminary studies suggest that this novel combination therapy may be effective in modulating the IDO pathway and in promoting long‐term immunity against lung cancer. NCI CA 13148–39 UAB CCC CDGP