Abstract
BackgroundCombination therapy based on radiotherapy and immune checkpoint inhibitors (ICIs) was recently reported as effective for various cancers. The radiation-induced immune response (RIIR) is an essential feature in ICI-combined radiotherapy; however, the effects of drugs used concomitantly with RIIR remain unclear. We screened for drugs that can modify RIIR to understand the mutual relationship between radiotherapy and combined drugs in ICI-combined radiotherapy.MethodsWe established a high-throughput system with reporter gene assays for evaluating RIIR, focusing on factors acting downstream of the STING-IRF pathway, which can stimulate cancer cells, T cells, and dendritic cells. We further quantified the effects of 2595 drugs, including those approved by the Food and Drug Administration, on RIIR in vitro.ResultsThe reporter assay results correlated well with the expression of immune response proteins such as programmed death-ligand 1. This high-throughput system enabled the identification of drugs including cytotoxic agents, molecular-targeted agents, and other agents that activate or suppress RIIR.ConclusionsOur study provides an encyclopedic catalogue of clinically approved drugs based on their effect on RIIR. In ICIs combined radiotherapy, activation of STING-IFN may improve the therapeutic effect and our result could form a biological basis for further clinical trials combining radiotherapy with ICIs.
Highlights
Combination therapy based on radiotherapy and immune checkpoint inhibitors (ICIs) was recently reported as effective for various cancers
reporter gene assay (RGA)-based validation of radiation-induced immune response (RIIR) assessment in A549-dual cells We investigated the validity of assessing the RIIR in cancer cells by performing an RGA
The protein expression of STATY701 and IFN-β, which have been reported as surrogates for the RIIR [25, 26], was assessed using Enzyme-linked immunosorbent assay (ELISA) and western blotting (Fig. 1b, c)
Summary
Radiotherapy (RT) is a widely used treatment for various cancers, including lung cancer [1], and recent data revealed that RT can enhance the efficacy of immune checkpoint inhibitors (ICIs) by upregulating MHC class I and programmed death-ligand 1 (PD-L1) expression in cancer cells [2]. As over 2000 drugs are currently approved, it is difficult to screen the effect of all drugs on the radiation-induced immune response (RIIR) through in vivo experiments. Radiation was shown to induce an immune reaction in the tumour tissue and surrounding immune cells via the micronucleus-forming STING-type I interferon (IFN) pathway in vitro and in vivo, which is considered as a master regulator of the cancer-immune reaction including the immune reaction in the tumour microenvironment (TME) triggered by irradiation [12]. Radiation activates the STING-IRFs-IFN pathway in cancer cells and activates surrounding immune cells [12]. We established a high-throughput system based on a In vitro irradiation reporter gene assay (RGA) for easy evaluation of the RIIR and screened the effect of a library of 2595 clinically approved agents on the RIIR. The cell culture, luciferase assay, and secreted alkaline day 3 (24 h after 4 Gy/2 fractions [fr]), day 5 (24 h after 8 Gy/4 fr), and day 8 a
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