Abstract
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.
Highlights
Two major goals in tumor vaccination are to induce regression of established tumors and to generate long-lasting tumor-specific immunity capable of protecting the host from relapse
Memory CD8 T cells are long-lived cells with heightened capacity to respond to subsequent insults that have been divided into two sub-populations, central memory T cells (TCM) and effector memory T cells (TEM), based on their expression of CCR7 and CD62L [1]
CD27 is a cell surface marker belonging to the tumor-necrosis factor receptor (TNFR) superfamily that is constitutively expressed on naıve CD8
Summary
Two major goals in tumor vaccination are to induce regression of established tumors and to generate long-lasting tumor-specific immunity capable of protecting the host from relapse. The ability to confer long-term protection in cancer has been limited largely by the inability to generate effective memory CD8 T cell responses. Memory CD8 T cells are endowed with unique properties that permit more vigorous and specific responses upon re-challenge to protect against tumor challenge. DNA vaccination would induce a robust population of both memory T cell subsets with the TEM acting as the initial defenders against tumor challenge and TCM replenishing the pool of TEM. Mam-A expression is similar on welldifferentiated, moderately differentiated, and poorly differentiated primary breast tumors [2,3]. This protein is frequently produced by metastatic breast cancer cells [2]
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