Toll-like receptor 3 signal augments radiation-induced tumor growth retardation in a murine model

Summary

Radiotherapy induces anti-tumor immunity by induction of tumor antigens and damage-associated molecular patterns (DAMPs). DNA, a representative DAMP in radiotherapy, activates the STING pathway which enhances the immune response. However, the immune response does not always parallel the inflammation associated with radiotherapy. This lack of correspondence may in part explain the radiation-resistance of tumors. Additive immunotherapy is expected to revive tumor-specific CTLs facilitating radiation-resistant tumor shrinkage. Herein pre-administration of the double-stranded RNA, polyI:C, in conjunction with radiotherapy, was demonstrated to foster tumor suppression in mice bearing radio-resistant, ovalbumin-expressing Lewis lung carcinoma (LLC). Extrinsic injection of tumor antigen was not required for the tumor suppression. No STING- and CTL- response was induced by radiation in the implant tumor. PolyI:C was more effective for induction of tumor growth retardation at one day before radiation than at post-treatment. PolyI:C targeted TLR3 with minimal effect on the MAVS pathway. Likewise, the STING pathway barely contributed to LLC tumor suppression. PolyI:C primed antigen-presenting dendritic cells (DCs) in draining lymph nodes to induce the proliferation of antigen-specific CTLs. By combination therapy, CTLs efficiently infiltrated into tumors with upregulation of relevant chemokine transcripts. Batf3-positive DCs and CD8⁺ T cells were essential for therapeutic efficacy. Furthermore, polyI:C was demonstrated to stimulate tumor-associated macrophages and release TNF-α, which acted on tumor cells and increased sensitivity to radiation. Hence, polyI:C treatment prior to radiotherapy potentially induces tumor suppression by boosting CTL-dependent and macrophage-mediated anti-tumor responses. Eventually, polyI:C and radiotherapy in combination would be a promising therapeutic strategy for radiation-resistant tumors.

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