Emergence of immune escape variant of mammary tumors that has distinct proteomic profile and a reduced ability to induce "danger signals".
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.
Manjili
Masoud H
MH
Department of Microbiology and Immunology, Virginia Commonwealth University, Massey Cancer Center, Richmond, VA, 23298, USA. mmanjili@vcu.edu
Arnouk
Hilal
H
Knutson
Keith L
KL
Kmieciak
Maciej
M
Disis
Mary L
ML
Subjeck
John R
JR
Kazim
A Latif
AL
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
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