Adoptive transfer of Mammaglobin-A epitope specific CD8 T cells combined with a single low dose of total body irradiation eradicates breast tumors.
Adoptive T cell therapy has proven to be beneficial in a number of tumor systems by targeting the relevant tumor antigen. The tumor antigen targeted in our model is Mammaglobin-A, expressed by approximately 80% of human breast tumors. Here we evaluated the use of adoptively transferred Mammaglobin-A specific CD8 T cells in combination with low dose irradiation to induce breast tumor rejection and prevent relapse. We show Mammaglobin-A specific CD8 T cells generated by DNA vaccination with all epitopes (Mammaglobin-A2.1, A2.2, A2.4 and A2.6) and full-length DNA in vivo resulted in heterogeneous T cell populations consisting of both effector and central memory CD8 T cell subsets. Adoptive transfer of spleen cells from all Mammaglobin-A2 immunized mice into tumor-bearing SCID/beige mice induced tumor regression but this anti-tumor response was not sustained long-term. Additionally, we demonstrate that only the adoptive transfer of Mammaglobin-A2 specific CD8 T cells in combination with a single low dose of irradiation prevents tumors from recurring. More importantly we show that this single dose of irradiation results in the down regulation of the macrophage scavenger receptor 1 on dendritic cells within the tumor and reduces lipid uptake by tumor resident dendritic cells potentially enabling the dendritic cells to present tumor antigen more efficiently and aid in tumor clearance. These data reveal the potential for adoptive transfer combined with a single low dose of total body irradiation as a suitable therapy for the treatment of established breast tumors and the prevention of tumor recurrence.
Rush University Medical Center, Department of Immunology and Microbiology, Chicago, Illinois, United States of America.
Nadine M
NM
Lerret
Magdalena
M
Rogozinska
Andrés
A
Jaramillo
Amanda L
AL
Marzo
D019264:Adoptive Transfer; D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D019041:L-Selectin / Q000378:metabolism; D050356:Lipid Metabolism; D060785:Mammaglobin A / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D019444:Vaccines, DNA / Q000276:immunology; D014916:Whole-Body Irradiation
D018984:Epitopes, T-Lymphocyte; D053699:Interleukin-7 Receptor alpha Subunit; D060785:Mammaglobin A; C495140:Msr1 protein, mouse; D051117:Scavenger Receptors, Class A; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D014409:Tumor Necrosis Factor-alpha; D019444:Vaccines, DNA; D019041:L-Selectin; D007371:Interferon-gamma