No abstract

T cell-based therapies have much promise in cancer treatment. This approach may be enhanced if used in combination with radiotherapy provided that tumorspecific T cells can be protected against the effects of radiotherapy. Previously, we demonstrated that administration of TLR9 ligand into mice decreased activation-and serum deprivation-induced cell death in T cells. We hypothesized that TLR9 engagement on T lymphocytes decreased apoptosis after cellular stress. We show that TLR9 engagement on murine CD4 T cells reduces ␥-radiation- IntroductionThe development of T cell-based immunotherapy to treat cancer patients has advanced significantly in the last decade due to the identification of multiple tumor antigens and the understanding of the signals that stimulate antitumor T-cell responses. 1 For example, vaccine-based strategies that incorporate tumor antigens (in the form of proteins or peptides) to elicit strong CD4 and CD8 T-cell responses are effective in both the prevention and the treatment of various cancers in preclinical studies. [2][3][4] In cancer patients, infusion of in vitro-activated and expanded tumor-specific T cells has been shown to reduce tumor burden in patients with various types of malignancies. 5 Unfortunately, although T-cell responses are effective against small tumor loads, they are generally ineffective against bulky tumors. 5 One promising strategy is to combine immunotherapy with current anticancer treatments to enhance the antitumor effects.Ionizing radiotherapy (RT) is an important therapy for the treatment of tumors. 6 Generally, RT is administered locally to the tumor site or draining lymph nodes and kills cancer cells by damaging DNA. Radiotherapy is effective at reducing large burdens in some cancers and preventing local recurrence in the case of positive margins. However, RT is rarely curative as a single treatment modality and is therefore often combined with chemotherapy. Unfortunately, this combination results in the destruction of nonmalignant cells including immune cells, which are especially sensitive to radiation. 7,8 Recent reports suggest that RT and immunotherapy might have a synergistic or at least an additive effect against tumors when given sequentially. [9][10][11][12][13] There might also be an advantage of giving the treatments at the same time, provided that tumor-specific T cells can be protected against the effects of RT. 14 The use of toll-like receptor (TLR) agonists as immune adjuvants to improve antitumor T-cell responses has been a subject of intense focus in recent times. Current studies reveal that local injections of TLR agonists can be combined with RT to enhance antitumor T-cell responses; however, these mechanisms remain undefined. [9][10][11][12][13] TLRs are expressed primarily on innate immune cells and activate the immune system by recognizing a range of microbial products, including lipopolysaccharide (TLR4), peptidoglycans and lipopeptides (TLR1 and TLR2), flagellin (TLR5), RNA (TLR3, TLR7, TLR8), and unmethylated "CpG"-DNA (TLR9). 15,16 S...