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

Abstract

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 CD8+ 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.

Weak Magnetic Fields Enhance the Efficacy of Radiation Therapy

“…LLC cells are also radioresistant and aggressively grow in syngeneic mice. 33 , 34 Figure 5 shows the results of irradiating LLC cells to 4 Gy at a range of magnetic field strengths. A clear relationship is observed between cell survival and field strength; the largest reduction in survival (20%) is observed near 40 G, but an increase in survival of more than 10% is observed for fields less than 20 G.

Figure 5 LLC survival using the gradient coils.

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The Role of Toll-Like Receptors in Oncotherapy

“…The application of the combination treatment decreases the dosage of administered chemotherapy, thereby reducing the side effects in patients and likely achieving better curative effects 58 . Yoshida et al reported that poly(I:C) treatment induces the proliferation of antigen-specific cytotoxic T-lymphocytes (CTLs) by antigen-presenting dendritic cells in draining lymph nodes, and the combination treatment of poly(I:C) with radiotherapy leads to an efficient infiltration of CTLs into tumors and the induction of relevant chemokine transcripts 59 . Moreover, poly(I:C)-activated tumor-associated macrophages led to the release of TNF-α, which can act on tumor cells and increase radiotherapy sensitivity.…”

Significance and Role of Pattern Recognition Receptors in Malignancy

“…The latter artificially produced, induce several wanted immune responses such as enhanced innate immunity and adaptive Th1 response (Krieg 2007). Polyinosinic–polycytydylic acid (poly:C) known to be the double-stranded RNA, able to act as the ligand of TLR3, was shown to inhibit growth of radioresistant Lewis lung carcinoma in mice, when applied in concern with radiotherapy (Yoshida et al 2018). Poly:C given in vivo epicutaneously into human skin resulted in the activation of PRRs in Langerhans cells and keratinocytes manifested by the induction of IFN-regulatory factor 3 and NF-κB (Tajpara et al 2018).…”