title: Emergence of immune escape variant of mammary tumors that has distinct proteomic profile and a reduced ability to induce "danger signals".
abstract: Breast tumors are shaped, in part, by a process termed immunoediting which selects for immunologically evasive phenotypes. In the present study we used the rat neu-transgenic mouse model of breast cancer and its congenic non-transgenic parental strain, FVB, to explore the phenotype of tumors that emerge in the presence of an immune response directed against the neu antigen. When inoculated into parental FVB mice, a neu-overexpressing mouse mammary carcinoma (MMC) cell line isolated from spontaneous breast tumors of the FVB neu (FVBN202) transgenic mouse, elicited a neu-specific immune response resulting in a tumor rejection because of the presence of the rat neu antigen. However, a neu negative variant (ANV) of MMC arose after a long latency in spite of the neu-specific immune response. We show that compared to MMC, ANV tumor cells have a significantly reduced ability to secrete pro-inflammatory cytokines and the CCL5 chemokine, to express immunostimulatory chaperones, and they have a distinct expression of proteins involved in cell motility, and metabolic and signal transduction pathways. These studies suggest that tumor escape through immunoediting can not be explained by the loss of a single tumor antigen, but rather by a selection process of a tumor variant that has a reduced ability to induce "danger signals" together with up-regulation of proteins involved in the tumor survival. Based on these findings, we propose to target novel antigens over-expressed in the escape variant of breast tumors to treat primary tumor and to prevent tumor relapse.
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Massey Cancer Center, Richmond, VA, 23298, USA. mmanjili@vcu.edu
authors.forename: Masoud H
authors.initials: MH
authors.lastname: Manjili
authors.forename: Hilal
authors.initials: H
authors.lastname: Arnouk
authors.forename: Keith L
authors.initials: KL
authors.lastname: Knutson
authors.forename: Maciej
authors.initials: M
authors.lastname: Kmieciak
authors.forename: Mary L
authors.initials: ML
authors.lastname: Disis
authors.forename: John R
authors.initials: JR
authors.lastname: Subjeck
authors.forename: A Latif
authors.initials: AL
authors.lastname: Kazim
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018946:Chemokine CCL5; D019742:Chemokines, CC / Q000096:biosynthesis; D051356:Cortactin / Q000032:analysis; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000276:immunology*; D051379:Mice; D009363:Neoplasm Proteins / Q000032:analysis*; D040901:Proteomics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology; D019139:Tumor Escape
chemical_list: D018946:Chemokine CCL5; D019742:Chemokines, CC; D051356:Cortactin; D016207:Cytokines; D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C503460:Ccl5 protein, mouse; C495869:Cttn protein, mouse