Blockade of the Complement C5a/C5aR1 Axis Impairs Lung Cancer Bone Metastasis by CXCL16-mediated Effects

Ajona, Daniel; Zandueta, Carolina; Corrales, Leticia; Moreno, Haritz; Pajares, María J.; Ortiz‐Espinosa, Sergio; Martínez-Terroba, Elena; Perurena, Naiara; Miguel, Fernando J. de; Jantus‐Lewintre, Eloísa; Camps, Carlos; Vicent, Silvestre; Agorreta, Jackeline; Montuenga, Luis M.; Pı́o, Rubén; Lecanda, Fernando

doi:10.1164/rccm.201703-0660oc

Cited by 60 publications

(59 citation statements)

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“…Gene expression and western blotting. Quantification of Igf1r and Hmox1 gene expression was performed by real-time PCR as described previously 32 . Gapdh was used as an endogenous control.…”

Section: Methodsmentioning

confidence: 99%

“…Human circulating levels of IGF-1 were measured using a Milliplex MAP kit (Millipore) with Luminex xMAP technology, following the manufacturer´s protocol. For IGF-1R immunohistochemical analysis, paraffin was removed and the endogenous peroxidase activity quenched as described previously 32 . Antigen retrieval was performed in a Lab Vision PT module for 20 min in EDTA buffer (pH 9) (Thermo Scientific).…”

Section: Methodsmentioning

confidence: 99%

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Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade

et al. 2020

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Harnessing the immune system by blocking the programmed cell death protein 1 (PD-1) pathway has been a major breakthrough in non-small-cell lung cancer treatment. Nonetheless, many patients fail to respond to PD-1 inhibition. Using three syngeneic models, we demonstrate that short-term starvation synergizes with PD-1 blockade to inhibit lung cancer progression and metastasis. This antitumor activity was linked to a reduction in circulating insulin-like growth factor 1 (IGF-1) and a downregulation of IGF-1 receptor (IGF-1R) signaling in tumor cells. A combined inhibition of IGF-1R and PD-1 synergistically reduced tumor growth in mice. This effect required CD8 cells, boosted the intratumoral CD8/T reg ratio and led to the development of tumor-specific immunity. In patients with non-small-cell lung cancer, high plasma levels of IGF-1 or high IGF-1R expression in tumors was associated with resistance to anti-PD-1-programmed death-ligand 1 immunotherapy. In conclusion, our data strongly support the clinical evaluation of IGF-1 modulators in combination with PD-1 blockade.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade

et al. 2020

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“…Metastatic potential of the A549-TM-YES1 (bioluminescence reporter vector) was evaluated by subcutaneous or intracardiac injection, as previously described (26).…”

Section: Analysis Of Metastatic Progressionmentioning

confidence: 99%

YES1 Drives Lung Cancer Growth and Progression and Predicts Sensitivity to Dasatinib

Garmendia

Pajares

Hermida-Prado

et al. 2019

Am J Respir Crit Care Med

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Rationale: The characterization of new genetic alterations is essential to assign effective personalized therapies in non-small cell lung cancer (NSCLC). Furthermore, finding stratification biomarkers is essential for successful personalized therapies. Molecular alterations of YES1, a member of the SRC (proto-oncogene tyrosine-protein kinase Src) family kinases (SFKs), can be found in a significant subset of patients with lung cancer. Objectives: To evaluate YES1 (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) genetic alteration as a therapeutic target and predictive biomarker of response to dasatinib in NSCLC. Methods: Functional significance was evaluated by in vivo models of NSCLC and metastasis and patient-derived xenografts. The efficacy of pharmacological and genetic (CRISPR [clustered regularly interspaced short palindromic repeats]/Cas9 [CRISPR-associated protein 9]) YES1 abrogation was also evaluated. In vitro functional assays for signaling, survival, and invasion were also performed. The association between YES1 alterations and prognosis was evaluated in clinical samples. Measurements and Main Results: We demonstrated that YES1 is essential for NSCLC carcinogenesis. Furthermore, YES1 overexpression induced metastatic spread in preclinical in vivo models. YES1 genetic depletion by CRISPR/Cas9 technology significantly reduced tumor growth and metastasis. YES1 effects were mainly driven by mTOR (mammalian target of rapamycin) signaling. Interestingly, cell lines and patient-derived xenograft models with YES1 gene amplifications presented a high sensitivity to dasatinib, an SFK inhibitor, pointing out YES1 status as a stratification biomarker for dasatinib response. Moreover, high YES1 protein expression was an independent predictor for poor prognosis in patients with lung cancer. Conclusions: YES1 is a promising therapeutic target in lung cancer. Our results provide support for the clinical evaluation of dasatinib treatment in a selected subset of patients using YES1 status as predictive biomarker for therapy.

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“…Our functional enrichment analysis suggests that the genes in our prognostic signature are widely involved in the immune process. Among all the 21 prognostic genes, 14 (e.g., AQP3, BIRC5, C5AR1, HMOX1, IL32, IL6ST, MIF, MMP12, PLAUR , PMAIP1, RAC1, SMAD6, SPHK1, USP7) have been reported to be served as a prognostic biomarker or suggested to be a novel therapeutic targets for lung adenocarcinoma [53][54][55][56][57][58][59][60][61][62][63][64][65][66][67]. The remaining 7 genes, including ARF6, C7, ELF4, ITPR1, MOV10, PTCH1 and RIPK2, have not been previously reported to be associated with LUAD prognosis and might act as potential biomarker.…”

Section: Discussionmentioning

confidence: 99%

Development and validation of a robust immune-related prognostic signature in early-stage lung adenocarcinoma

Zheng

Wang

et al. 2020

J Transl Med

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Background The incidence of stage I and stage II lung adenocarcinoma (LUAD) is likely to increase with the introduction of annual screening programs for high-risk individuals. We aimed to identify a reliable prognostic signature with immune-related genes that can predict prognosis and help making individualized management for patients with early-stage LUAD. Methods The public LUAD cohorts were obtained from the large-scale databases including 4 microarray data sets from the Gene Expression Omnibus (GEO) and 1 RNA-seq data set from The Cancer Genome Atlas (TCGA) LUAD cohort. Only early-stage patients with clinical information were included. Cox proportional hazards regression model was performed to identify the candidate prognostic genes in GSE30219, GSE31210 and GSE50081 (training set). The prognostic signature was developed using the overlapped prognostic genes based on a risk score method. Kaplan–Meier curve with log-rank test and time-dependent receiver operating characteristic (ROC) curve were used to evaluate the prognostic value and performance of this signature, respectively. Furthermore, the robustness of this prognostic signature was further validated in TCGA-LUAD and GSE72094 cohorts. Results A prognostic immune signature consisting of 21 immune-related genes was constructed using the training set. The prognostic signature significantly stratified patients into high- and low-risk groups in terms of overall survival (OS) in training data set, including GSE30219 (HR = 4.31, 95% CI 2.29–8.11; P = 6.16E−06), GSE31210 (HR = 11.91, 95% CI 4.15–34.19; P = 4.10E−06), GSE50081 (HR = 3.63, 95% CI 1.90–6.95; P = 9.95E−05), the combined data set (HR = 3.15, 95% CI 1.98–5.02; P = 1.26E−06) and the validation data set, including TCGA-LUAD (HR = 2.16, 95% CI 1.49–3.13; P = 4.54E−05) and GSE72094 (HR = 2.95, 95% CI 1.86–4.70; P = 4.79E−06). Multivariate cox regression analysis demonstrated that the 21-gene signature could serve as an independent prognostic factor for OS after adjusting for other clinical factors. ROC curves revealed that the immune signature achieved good performance in predicting OS for early-stage LUAD. Several biological processes, including regulation of immune effector process, were enriched in the immune signature. Moreover, the combination of the signature with tumor stage showed more precise classification for prognosis prediction and treatment design. Conclusions Our study proposed a robust immune-related prognostic signature for estimating overall survival in early-stage LUAD, which may be contributed to make more accurate survival risk stratification and individualized clinical management for patients with early-stage LUAD.

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Blockade of the Complement C5a/C5aR1 Axis Impairs Lung Cancer Bone Metastasis by CXCL16-mediated Effects

Abstract: Disruption of C5aR1 signaling in lung cancer cells abrogates their tumor-associated osteoclastogenic activity, impairing osseous colonization. This study unveils the role played by the C5a/C5aR1 axis in lung cancer dissemination and supports its potential use as a novel therapeutic target.

Cited by 60 publications

References 50 publications

Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade

Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade

YES1 Drives Lung Cancer Growth and Progression and Predicts Sensitivity to Dasatinib

Development and validation of a robust immune-related prognostic signature in early-stage lung adenocarcinoma

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