Dendritic cells (DC) perform an essential role in the generation and regulation of antitumor immune responses. It is therefore not surprising that many tumors have evolved mechanisms that alter DC activity and function. Our recent work indicates that the generation, maturation, function, and longevity of DC are all markedly inhibited in cancer. However, molecular mechanisms and intracellular pathways that are involved in the inhibition of DC differentiation and maturation in cancer have not yet been explored. Awareness of these mechanisms will help to direct development of the next generation of tumor vaccines. Novel therapies that can correct DC dysfunction without compromising normal host cell-mediated immunity are desirable. Hence, the identification of potential molecular targets in DC and/or DC precursors, amenable to therapeutic manipulation, is critical. Our main goal is to determine how tumor escapes immune recognition in order to uncover useful molecular targets for the therapeutic protection of the immune system. The purpose of this application is to characterize novel molecular mechanisms that inhibit DC maturation in cancer. Our major hypothesis is that the small Rho GTPases from the Ras superfamily of GTP-binding proteins are important tumor targets that are responsible for regulating DC maturation and function in the tumor microenvironment. On the basis of our preliminary data, we also hypothesize that the dysbalance of DC maturation induced by tumors is associated with impaired endocytosis, migration, adhesion, chemotaxis, and antigen processing and presentation by DC and that Rho GTPases are directly involved in these phenomena. We propose to evaluate tumor-mediated regulation of Rho, Rac, and Cdc42 in DC and their role in regulating DC maturation and function in cancer. To test our hypotheses, we will pursue four Specific Aims: 1. Identify pathways involved in inhibiting DC maturation and function in the tumor microenvironment by identifying GTP-GDP cycling-dependent and -independent mechanisms that regulate Rho GTPases in DC. 2. Assess the effect that specific signaling pathways have on deficient DC maturation in cancer by evaluating the role of small Rho GTPases in regulating DC function. 3. Identify signaling to Rho GTPases in DC in cancer by comparing and contrasting the effects of purified DC suppressing tumor-derived factors and DC activating cytokines. 4. Evaluate the therapeutic feasibility of targeting the Rho GTPase network in DC using animal tumor models. By accomplishing these aims, we will have proposed a new molecular mechanism of the regulation of dendropoiesis in cancer. Additionally, understanding the mechanisms responsible for DC dysfunction in cancer will serve as a basis for developing novel therapeutic approaches for patients with cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA084270-04A2
Application #
6725209
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Howcroft, Thomas K
Project Start
2000-02-18
Project End
2009-01-31
Budget Start
2004-02-16
Budget End
2005-01-31
Support Year
4
Fiscal Year
2004
Total Cost
$266,360
Indirect Cost
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Malyguine, Anatoli; Umansky, Victor; Kotlan, Beatrix et al. (2012) Conference overview: Cancer Immunotherapy and Immunomonitoring (CITIM): moving forward. J Immunotoxicol 9:231-5
Kaneno, Ramon; Shurin, Galina V; Kaneno, Felipe M et al. (2011) Chemotherapeutic agents in low noncytotoxic concentrations increase immunogenicity of human colon cancer cells. Cell Oncol (Dordr) 34:97-106
Song, Eun Young; Shurin, Michael R; Tourkova, Irina L et al. (2010) Epigenetic mechanisms of promigratory chemokine CXCL14 regulation in human prostate cancer cells. Cancer Res 70:4394-401
Kaneno, Ramon; Shurin, Galina V; Tourkova, Irina L et al. (2009) Chemomodulation of human dendritic cell function by antineoplastic agents in low noncytotoxic concentrations. J Transl Med 7:58
Shurin, Michael R; Potapovich, Alla I; Tyurina, Yulia Y et al. (2009) Recognition of live phosphatidylserine-labeled tumor cells by dendritic cells: a novel approach to immunotherapy of skin cancer. Cancer Res 69:2487-96
Tourkova, Irina L; Shurin, Galina V; Ferrone, Soldano et al. (2009) Interferon regulatory factor 8 mediates tumor-induced inhibition of antigen processing and presentation by dendritic cells. Cancer Immunol Immunother 58:567-74
Malyguine, Anatoli; Umansky, Victor; Shurin, Michael R (2009) Cancer immunotherapy and immunomonitoring (CITIM): redefining cancer therapy. J Immunotoxicol 6:205-8
Shurin, Galina V; Tourkova, Irina L; Kaneno, Ramon et al. (2009) Chemotherapeutic agents in noncytotoxic concentrations increase antigen presentation by dendritic cells via an IL-12-dependent mechanism. J Immunol 183:137-44
Shurin, Galina V; Tourkova, Irina L; Shurin, Michael R (2008) Low-dose chemotherapeutic agents regulate small Rho GTPase activity in dendritic cells. J Immunother 31:491-9
Shurin, Michael R; Shurin, Galina V; Chatta, Gurkamal S (2007) Aging and the dendritic cell system: implications for cancer. Crit Rev Oncol Hematol 64:90-105

Showing the most recent 10 out of 38 publications