Abstract
Immune responses contribute to the success of radiotherapy of solid tumors; however, the mechanism of triggering CD8(+) T-cell responses is poorly understood. Antigen cross-presentation from tumor cells by dendritic cells (DC) is a likely dominant mechanism to achieve CD8(+) T-cell stimulation. We established a cross-presentation model in which DCs present a naturally expressed oncofetal tumor antigen (5T4) from irradiated DU145 prostate cancer cells to 5T4-specific T cells. The aim was to establish which immunogenic signals are important in radiation-induced cross-presentation. Radiation (12 Gy) caused G2-M cell-cycle arrest and cell death, increased cellular 5T4 levels, high-mobility protein group-B1 (HMGB1) release, and surface calreticulin and heat-shock protein-70 (Hsp70) expression in DU145 cells. DCs phagocytosed irradiated tumor cells efficiently, followed by upregulation of CD86 on phagocytic DCs. CD8(+) 5T4-specific T cells, stimulated with these DCs, proliferated and produced IFNγ. Inhibition of HMGB1 or the TRIF/MyD88 pathway only had a partial effect on T-cell stimulation. Unlike previous investigators, we found no evidence that DCs carrying Asp299Gly Toll-like receptor-4 (TLR4) single-nucleotide polymorphism had impaired ability to cross-present tumor antigen. However, pretreatment of tumor cells with Hsp70 inhibitors resulted in a highly statistically significant and robust prevention of antigen cross-presentation and CD86 upregulation on DCs cocultured with irradiated tumor cells. Blocking the Hsp70 receptor CD91 also abolished cross-presentation. Together, the results from our study demonstrate that irradiation induces immunologically relevant changes in tumor cells, which can trigger CD8(+) T-cell responses via a predominantly Hsp70-dependent antigen cross-presentation process.
Highlights
Traditional treatments of cancer, such as surgery, chemotherapy, and radiotherapy, have been shown to trigger immune responses, which may contribute toward treatment outcome
We found no evidence that dendritic cells (DC) carrying Asp299Gly Toll-like receptor-4 (TLR4) single-nucleotide polymorphism had impaired ability to cross-present tumor antigen
We found that heat-shock protein-70 (Hsp70) is crucially important both in activating DCs and triggering CD8þ T-cell responses to DCs cocultured with irradiated tumor cells
Summary
Traditional treatments of cancer, such as surgery, chemotherapy, and radiotherapy, have been shown to trigger immune responses, which may contribute toward treatment outcome. Radiation is curative in up to 40% of patients with early-stage (localized) prostate cancer, but it is not yet clear what are the predictors of complete responses. Radiotherapy in prostate cancer has been shown to be associated with increased frequencies of tumor antigen-specific T cells [1]. The abscopal effect of radiation (tumor regression at a distant site following localized radiation) has been shown to be immune mediated. Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/). CD8þ T-cell infiltration in the irradiated tumor tissue serves as a prognostic factor [4,5,6,7], indicating that radiation can switch the immunosuppressive tumor milieu to a proimmune environment
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