Open AccessToll‐like receptor 3 signal augments radiation‐induced tumor growth retardation in a murine model
Author(s) -
Yoshida Sumito,
Shime Hiroaki,
Takeda Yohei,
Nam JinMin,
Takashima Ken,
Matsumoto Misako,
Shirato Hiroki,
Kasahara Masanori,
Seya Tsukasa
Publication year - 2018
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13543
Subject(s) - cancer research , radioresistance , immune system , ctl* , tlr3 , tumor necrosis factor alpha , biology , immunotherapy , antigen , immunology , radiation therapy , medicine , toll like receptor , innate immune system , cd8
Radiotherapy induces anti‐tumor immunity by induction of tumor antigens and damage‐associated molecular patterns ( DAMP ). DNA , a representative DAMP in radiotherapy, activates the stimulator of interferon genes ( 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 CTL facilitating radiation‐resistant tumor shrinkage. Herein pre‐administration of the double‐stranded RNA , polyinosinic‐polycytidylic acid (polyI:C), in conjunction with radiotherapy, was shown to foster tumor suppression in mice bearing radioresistant, ovalbumin‐expressing Lewis lung carcinoma ( LLC ). Extrinsic injection of tumor antigen was not required for 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 1 day before radiation than at post‐treatment. PolyI:C targeted Toll‐like receptor 3 with minimal effect on the mitochondrial antiviral‐signaling protein pathway. Likewise, the STING pathway barely contributed to LLC tumor suppression. PolyI:C primed antigen‐presenting dendritic cells in draining lymph nodes to induce proliferation of antigen‐specific CTL . By combination therapy, CTL efficiently infiltrated into tumors with upregulation of relevant chemokine transcripts. Batf3‐positive DC and CD 8 + T cells were essential for therapeutic efficacy. Furthermore, polyI:C was shown to stimulate tumor‐associated macrophages and release tumor necrosis factor alpha, 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.