Cellular Atlas of Senescent Lineages in Radiation- or Immunotherapy-Induced Lung Injury by Single-Cell RNA-Sequencing Analysis

Wu, Fei; Zhang, Zengfu; Wang, Minglei; Ma, Yuequn; Verma, Vivek; Xiao, Changyang; Tao, Zhong; Chen, Xiaozheng; Wu, Meng; Yu, Jiang; Chen, Fan

doi:10.1016/j.ijrobp.2023.02.005

Cited by 11 publications

(7 citation statements)

References 44 publications

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“…Characterized by high Ccl8 expression, Mac_Ccl8 facilitates the recruitment of other macrophages via the CCL signaling pathway. A recent study has highlighted hypofractionated radiotherapy-induced senescence signatures in macrophages, including genes such as Ccl8, Ccl2, Ccl7, Apoe, and Csf1r[40]. The Mac_Ccl8 subpopulation in our study also highly expressed these genes, which relates with worse overall outcomes in NSCLC patients.…”

Section: Discussionsupporting

confidence: 49%

Single-cell RNA sequencing reveals recruitment of the M2-like CCL8^highmacrophages in Lewis lung carcinoma-bearing mice following hypofractionated radiotherapy

Yang,

Lei,

et al. 2024

Preprint

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Tumor-associated macrophages (TAMs) are a crucial factor in reprogramming the tumor microenvironment following radiotherapy. The mechanisms underlying this process remain to be elucidated. Here, we seek to investigate the effects of hypofractionated radiotherapy on macrophages dynamics in a subcutaneous Lewis lung carcinoma murine model. Utilizing single-cell RNA sequencing, we identified a distinct M2-like population of macrophages with high Ccl8 expression level post-hypofractionated radiotherapy. Remarkbly, hypofractionated radiotherapy promoted CCL8highmacrophages infiltration and reprogrammed them by upregulating immunosuppressive genes and downregulating antigen-presenting genes, leading to an immunosuppressive tumor microenvironment. Further, we demonstrated that hypofractionated radiotherapy amplified the CCL signaling pathway, enhancing the pro-tumorigenic functions of CCL8highmacrophages and promoting macrophages recruitment. The combination therapy of hypofractionated radiotherapy with the CCL signal inhibitor Bindarit was effective in reducing M2 macrophages infiltration and extending the duration of local tumor control. This research highlights the potential of targeting TAMs and introduces a novel combination to improve the efficacy of hypofractionated radiotherapy.

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Section: Discussionsupporting

confidence: 49%

Single-cell RNA sequencing reveals recruitment of the M2-like CCL8^highmacrophages in Lewis lung carcinoma-bearing mice following hypofractionated radiotherapy

Yang,

Lei,

et al. 2024

Preprint

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“…Yao C et al conducted sequencing analysis of epithelial cells from both control and IPF patient fibrotic lung tissue, revealing that ATII cells isolated from the latter exhibited distinct transcriptomic features associated with cell senescence and that the senescence of ATII cells is adequate to induce lung fibrosis [ 34 ]. Additionally, Wu F et al illustrated that the accumulation of senescence-like lung fibroblasts serves as a major pathological mechanism in lung injury caused by immune and radiation therapy [ 35 ]. Notably, the selective elimination of senescent lung fibroblasts using dasatinib plus quercetin could alleviate mouse lung fibrosis and improve lung function [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

“…Cell senescence, recognized as a hallmark of aging, is characterized by an irreversible arrest of the cell cycle induced by a variety of intrinsic and extrinsic stimuli [31,32]. Single-cell RNA sequencing identified multiple cell types in the lung tissue of fibrotic patients, such as epithelial cells, fibroblasts, and macrophages, displaying a senescence-like phenotype [33][34][35][36]. Yao C et al conducted sequencing analysis of epithelial cells from both control and IPF patient fibrotic lung tissue, revealing that ATII cells isolated from the latter exhibited distinct transcriptomic features associated with cell senescence and that the senescence of ATII cells is adequate to induce lung fibrosis [34].…”

Section: Discussionmentioning

confidence: 99%

NR2F2 alleviates pulmonary fibrosis by inhibition of epithelial cell senescence

Wan,

Long,

et al. 2024

Respir Res

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Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fatal, and aging-associated interstitial lung disease with a poor prognosis and limited treatment options, while the pathogenesis remains elusive. In this study, we found that the expression of nuclear receptor subfamily 2 group F member 2 (NR2F2), a member of the steroid thyroid hormone superfamily of nuclear receptors, was reduced in both IPF and bleomycin-induced fibrotic lungs, markedly in bleomycin-induced senescent epithelial cells. Inhibition of NR2F2 expression increased the expression of senescence markers such as p21 and p16 in lung epithelial cells, and activated fibroblasts through epithelial-mesenchymal crosstalk, inversely overexpression of NR2F2 alleviated bleomycin-induced epithelial cell senescence and inhibited fibroblast activation. Subsequent mechanistic studies revealed that overexpression of NR2F2 alleviated DNA damage in lung epithelial cells and inhibited cell senescence. Adenovirus-mediated Nr2f2 overexpression attenuated bleomycin-induced lung fibrosis and cell senescence in mice. In summary, these data demonstrate that NR2F2 is involved in lung epithelial cell senescence, and targeting NR2F2 may be a promising therapeutic approach against lung cell senescence and fibrosis.

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“…Characterized by high Ccl8 expression, Mac_Ccl8 facilitates the recruitment of other macrophages via the CCL signaling pathway. A recent study has highlighted hypofractionated radiotherapy-induced senescence signatures in macrophages, including genes such as Ccl8, Ccl2, Ccl7, Apoe, and Csf1r [ 45 ]. The Mac_Ccl8 subpopulation in our study also highly expressed these genes, which relates with worse overall outcomes in NSCLC patients.…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing reveals recruitment of the M2-like CCL8high macrophages in Lewis lung carcinoma-bearing mice following hypofractionated radiotherapy

Yang,

Lei,

et al. 2024

J Transl Med

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Background Tumor-associated macrophages (TAMs) play a pivotal role in reshaping the tumor microenvironment following radiotherapy. The mechanisms underlying this reprogramming process remain to be elucidated. Methods Subcutaneous Lewis lung carcinoma (LLC) murine model was treated with hypofrationated radiotherapy (8 Gy × 3F). Single-cell RNA sequencing was utilized to identify subclusters and functions of TAMs. Multiplex assay and enzyme-linked immunosorbent assay (ELISA) were employed to measure serum chemokine levels. Bindarit was used to inhibit CCL8, CCL7, and CCL2. The infiltration of TAMs after combination treatment with hypofractionated radiotherapy and Bindarit was quantified with flow cytometry, while the influx of CD206 and CCL8 was assessed by immunostaining. Results Transcriptome analysis identified a distinct subset of M2-like macrophages characterized by elevated Ccl8 expression level following hypofractionated radiotherapy in LLC-bearing mice. Remarkbly, hypofractionated radiotherapy not only promoted CCL8high macrophages infiltration but also reprogrammed them by upregulating immunosuppressive genes, thereby fostering an immunosuppressive tumor microenvironment. Additioinally, hypofractionated radiotherapy enhanced the CCL signaling pathway, augmenting the pro-tumorigenic functions of CCL8high macrophages and boosting TAMs recruitment. The adjunctive treatment combining hypofractionated radiotherapy with Bindarit effectively reduced M2 macrophages infiltration and prolonged the duration of local tumor control. Conclusions Hypofractionated radiotherapy enhances the infiltration of CCL8high macrophages and amplifies their roles in macrophage recruitment through the CCL signaling pathway, leading to an immunosuppressive tumor microenvironment. These findings highlight the potential of targeting TAMs and introduces a novel combination to improve the efficacy of hypofractionated radiotherapy.

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Cellular Atlas of Senescent Lineages in Radiation- or Immunotherapy-Induced Lung Injury by Single-Cell RNA-Sequencing Analysis

Cited by 11 publications

References 44 publications

Single-cell RNA sequencing reveals recruitment of the M2-like CCL8^highmacrophages in Lewis lung carcinoma-bearing mice following hypofractionated radiotherapy

Single-cell RNA sequencing reveals recruitment of the M2-like CCL8^highmacrophages in Lewis lung carcinoma-bearing mice following hypofractionated radiotherapy

NR2F2 alleviates pulmonary fibrosis by inhibition of epithelial cell senescence

Single-cell RNA sequencing reveals recruitment of the M2-like CCL8high macrophages in Lewis lung carcinoma-bearing mice following hypofractionated radiotherapy

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Cellular Atlas of Senescent Lineages in Radiation- or Immunotherapy-Induced Lung Injury by Single-Cell RNA-Sequencing Analysis

Cited by 11 publications

References 44 publications

Single-cell RNA sequencing reveals recruitment of the M2-like CCL8highmacrophages in Lewis lung carcinoma-bearing mice following hypofractionated radiotherapy

Single-cell RNA sequencing reveals recruitment of the M2-like CCL8highmacrophages in Lewis lung carcinoma-bearing mice following hypofractionated radiotherapy

NR2F2 alleviates pulmonary fibrosis by inhibition of epithelial cell senescence

Single-cell RNA sequencing reveals recruitment of the M2-like CCL8high macrophages in Lewis lung carcinoma-bearing mice following hypofractionated radiotherapy

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Single-cell RNA sequencing reveals recruitment of the M2-like CCL8^highmacrophages in Lewis lung carcinoma-bearing mice following hypofractionated radiotherapy

Single-cell RNA sequencing reveals recruitment of the M2-like CCL8^highmacrophages in Lewis lung carcinoma-bearing mice following hypofractionated radiotherapy