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Objective Immune checkpoint inhibitors (ICIs) have become the standard of care in various cancers, although the predictive tool is still unknown. Methods This study aimed to develop a novel gene panel by selecting DNA damage response (DDR) genes from the Catalogue of Somatic Mutations in Cancer (COSMIC) databank and validating them in previously reported cohorts. This association between DDR gene mutations and tumor mutation burden or microsatellite status was analysed from The Cancer Genome Atlas (TCGA) databank. Furthermore, we made the gene panel clinically accessible and predicted the response in clinical patients receiving ICIs by using cell‐free DNA. Results The top 20 mutated DDR genes in various cancers (total 37 genes) were taken from the COSMIC databank, and the DDR genes found to individually predict a response rate > 50% in Van Allen's cohort were selected (Science, 350, 2015 and 207). Eighteen DDR genes were selected as the gene panel. The prevalence and predicted response rate were validated in the other three reported cohorts. Tumor mutational burden‐high was positively associated with mutations of the 18 DDR genes for most cancers. We used cell‐free DNA to test the DDR gene panel and validated by our patients receiving ICIs. This DDR gene panel accounted for approximately 30% of various cancers, achieving a predicted response rate of approximately 60% in patients with a mutated gene panel receiving ICIs. Conclusion This gene panel is a novel and reliable tool for predicting the response to ICIs in cancer patients and guides the appropriate administration of ICIs in clinical practice., Immune checkpoint inhibitors (ICIs) have been widely used to treat various cancers and have achieved impressive success, resulting in a new era of anticancer therapy. However, only a subset of patients experienced lasting responses; therefore, exploring predictive biomarkers is critical to identify the patients who have benefit from ICIs. This gene panel using liquid biopsy is one of the best predictive biomarkers presently available and can help physicians to predict the response to ICIs and judge the utility of ICIs in clinical practice.

Objective Prolonged glucocorticoid treatment increases the risk of osteopenic disorders. Bone loss and marrow fat accumulation are prominent features of glucocorticoid-induced skeletal destruction. Cannabinoid receptor 1 (CB1) has been found to regulate energy expenditure and adipose tissue lipogenesis. We undertook this study to investigate whether CB1 signaling regulates glucocorticoid-induced bone loss. Methods Rats were administered glucocorticoid, CB1 antisense oligonucleotide, CB1 sense oligonucleotide, or the CB1 antagonist AM251. Bone mineral density, microstructure, biomechanical strength, and signaling transduction were assessed by dual x-ray absorptiometry, micro–computed tomography, material testing, and immunoblotting, respectively. Primary bone marrow stromal cells were isolated for assessment of ex vivo osteoblast and adipocyte differentiation. Results Glucocorticoid administration accelerated bone deterioration and fatty marrow formation in association with up-regulation of CB1 expression. Genetic and pharmacologic blockade of CB1 by CB1 antisense oligonucleotide and AM251 attenuated the deleterious effects of glucocorticoid treatment on bone mineral density, trabecular microarchitecture, and mechanical properties. CB1 antagonism improved osteoblast survival, osteoblast surface, and bone mineral acquisition, but abrogated marrow adiposity. Knockdown of CB1 restored osteogenic differentiation capacity and attenuated the promoting effects of glucocorticoid on adipogenic differentiation in primary bone marrow mesenchymal cells. CB1 signaling modulated ERK, JNK, and Akt activation as well as runt-related transcription factor 2 and peroxisome proliferator–activated receptor γ2 signaling. Adiponectin signaling was activated by CB1 regulation of bone formation and fatty marrow. Conclusion CB1 mediates glucocorticoid-induced suppression of bone formation and marrow fat homeostasis. CB1 antagonism reduces adipogenic and apoptotic reactions in bone microenvironments, thereby abrogating the deleterious effects of glucocorticoid treatment on bone integrity. Modulation of CB1 signaling has therapeutic potential for preventing glucocorticoid-induced osteopenic disorders.