The role of PD-1/PD-L1 axis in idiopathic pulmonary fibrosis: Friend or foe?

Jiang, Aimin; Liu, Na; Wang, Jingjing; Zheng, Xiaoqiang; Ren, Mengdi; Zhang, Wei; Yao, Yu

doi:10.3389/fimmu.2022.1022228

Cited by 8 publications

(5 citation statements)

References 165 publications

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“…Currently, the most common approach to replicate the pathological process of human IPF in C57BL/6 mice involves intratracheal injection of the cytotoxic drug bleomycin. 44,45 In our study, 5 mg/kg of bleomycin or an equal amount of PBS was intranasally introduced to male C57BL/6 mice three times. Subsequently, after 5 days of bleomycin or PBS injection, 1 × 10 6 LLC cells were intravenously inoculated into the mice to establish the orthotopic murine model of LUAD with coexistent IPF (LC-PF) or without (LC).…”

Section: Methodsmentioning

confidence: 99%

Advancing the Boundaries of Immunotherapy in Lung Adenocarcinoma with Idiopathic Pulmonary Fibrosis by a Biomimetic Proteinoid Enabling Selective Endocytosis

Jiang,

Zheng,

Yan

et al. 2024

ACS Nano

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The coexistence of lung adenocarcinoma (LUAD) with idiopathic pulmonary fibrosis (IPF), which has been extensively documented as a prominent risk factor for checkpoint inhibitor-related pneumonitis (CIP) in patients undergoing immunotherapy, has long been considered a restricted domain for the use of immune checkpoint inhibitors (ICIs). To overcome it, an approach was employed herein to specifically target PD-L1 within the cellular interior, surpassing the conventional focus solely on the cytomembrane, thereby facilitating the development of ICIs capable of distinguishing between LUAD cells and noncancerous cells based on their distinctive endocytic propensities. By exploiting the aurophilicity-driven self-assembly of a PD-L1 binding peptide (PDBP) and subsequently encapsulating it within erythrocyte membranes (EM), the resulting biomimetic ICIs protein EMS-PDBP exhibited extraordinary selectivity in internalizing LUAD cells, effectively targeting PD-L1 within cancer cells while hindering its membrane translocation. The EMS-PDBP treatment not only reactivated the antitumor immune response in the LUAD orthotopic allograft mouse model but also demonstrated a favorable safety profile by effectively eliminating any immunerelated adverse events (irAEs). Most significantly, EMS-PDBP successfully and safely restored the antitumor immune response in a mouse model of LUAD with coexistent IPF, thus shattering the confines of ICIs immunotherapy. The reported EMS-PDBP collectively offers a potential strategy for immune reactivation to overcome the limitations of immunotherapy in LUAD coexisting with IPF.

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Section: Methodsmentioning

confidence: 99%

Advancing the Boundaries of Immunotherapy in Lung Adenocarcinoma with Idiopathic Pulmonary Fibrosis by a Biomimetic Proteinoid Enabling Selective Endocytosis

Jiang,

Zheng,

Yan

et al. 2024

ACS Nano

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“…These investigators also reported that the expression of PD-L1 was clearly increased in the lungs of patients with idiopathic pulmonary fibrosis (IPF). It is known that the PD-1/PD-L1 signaling pathway has a crucial profibrotic role in the development of IPF disease [ 22 , 47 ], although it is not known whether it is caused by intrinsic or extrinsic regulation. Interestingly, Gao et al [ 48 ] demonstrated that the acetylation of the PD-L1 protein at Lys263 within its cytoplasmic tail regulated the translocation of the PD-L1 protein from the cell-surface into the nucleus.…”

Section: The Immunosuppressive Pd-1/pd-l1 Checkpoint Pathwaymentioning

confidence: 99%

“…The differentiation of tissue fibroblasts into fibrogenic myofibroblasts and an increase in the numbers of senescent fibroblasts are the major hallmarks of fibrotic lesions [ 75 , 80 ]. Emerging studies have revealed that the function of the PD-1/PD-L1 axis has a crucial role in the accumulation of fibrotic lesions [ 22 , 47 ]. There are a number of investigations indicating that in mouse and human fibrotic tissues, there exists a robust increase in the expression of PD-L1 protein not only in fibroblasts but also in endothelial and epithelial cells [ 18 , 22 , 44 , 47 , 81 ].…”

Section: Pd-1/pd-l1 Signaling Is Augmented In Many Age-related Diseasesmentioning

confidence: 99%

“…Emerging studies have revealed that the function of the PD-1/PD-L1 axis has a crucial role in the accumulation of fibrotic lesions [ 22 , 47 ]. There are a number of investigations indicating that in mouse and human fibrotic tissues, there exists a robust increase in the expression of PD-L1 protein not only in fibroblasts but also in endothelial and epithelial cells [ 18 , 22 , 44 , 47 , 81 ]. Onorati et al [ 18 ] utilized a single-cell transcriptome technique to determine in human interstitial lung fibrosis that the high expression of PD-L1 protein was localized into senescent cells which also displayed a proinflammatory phenotype.…”

Section: Pd-1/pd-l1 Signaling Is Augmented In Many Age-related Diseasesmentioning

confidence: 99%

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The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases

Salminen

2024

J Mol Med

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The accumulation of senescent cells within tissues is a hallmark of the aging process. Senescent cells are also commonly present in many age-related diseases and in the cancer microenvironment. The escape of abnormal cells from immune surveillance indicates that there is some defect in the function of cytotoxic immune cells, e.g., CD8+ T cells and natural killer (NK) cells. Recent studies have revealed that the expression of programmed death-ligand 1 (PD-L1) protein is abundantly increased in senescent cells. An increase in the amount of PD-L1 protein protects senescent cells from clearance by the PD-1 checkpoint receptor in cytotoxic immune cells. In fact, the activation of the PD-1 receptor suppresses the cytotoxic properties of CD8+ T and NK cells, promoting a state of immunosenescence. The inhibitory PD-1/PD-L1 checkpoint pathway acts in cooperation with immunosuppressive cells; for example, activation of PD-1 receptor can enhance the differentiation of regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and M2 macrophages, whereas the cytokines secreted by immunosuppressive cells stimulate the expression of the immunosuppressive PD-L1 protein. Interestingly, many signaling pathways known to promote cellular senescence and the aging process are crucial stimulators of the expression of PD-L1 protein, e.g., epigenetic regulation, inflammatory mediators, mTOR-related signaling, cGAS-STING pathway, and AhR signaling. It seems that the inhibitory PD-1/PD-L1 immune checkpoint axis has a crucial role in the accumulation of senescent cells and thus it promotes the aging process in tissues. Thus, the blockade of the PD-1/PD-L1 checkpoint signaling might be a potential anti-aging senolytic therapy. Key messages Senescent cells accumulate within tissues during aging and age-related diseases. Senescent cells are able to escape immune surveillance by cytotoxic immune cells. Expression of programmed death-ligand 1 (PD-L1) markedly increases in senescent cells. Age-related signaling stimulates the expression of PD-L1 protein in senescent cells. Inhibitory PD-1/PD-L1 checkpoint pathway suppresses clearance of senescent cells.

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“…Emerging literature highlights the potential of PDL1 inhibition in reducing fibrosis severity in pulmonary fibrosis, and the PDL1 pathway mainly plays a role in promoting fibrosis rather than its immunomodulatory role ( 84 ). The fibrotic effect of PDL1 in IPF arises from intricate cellular interactions and signaling pathways, with the following mechanisms assuming paramount significance( Figure 4 ): firstly, overexpression of PDL1 in lung fibroblasts exerts resistance to myoblast apoptosis and eludes macrophage phagocytosis via the inhibition of p53 pathway or activation of FAK pathway.…”

Section: The Multifunctional Role Of Pdl1 In Emt: From Immune Evasion...mentioning

confidence: 99%

What role does PDL1 play in EMT changes in tumors and fibrosis?

et al. 2023

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Epithelial-mesenchymal transformation (EMT) plays a pivotal role in embryonic development, tissue fibrosis, repair, and tumor invasiveness. Emerging studies have highlighted the close association between EMT and immune checkpoint molecules, particularly programmed cell death ligand 1 (PDL1). PDL1 exerts its influence on EMT through bidirectional regulation. EMT-associated factors, such as YB1, enhance PDL1 expression by directly binding to its promoter. Conversely, PDL1 signaling triggers downstream pathways like PI3K/AKT and MAPK, promoting EMT and facilitating cancer cell migration and invasion. Targeting PDL1 holds promise as a therapeutic strategy for EMT-related diseases, including cancer and fibrosis. Indeed, PDL1 inhibitors, such as pembrolizumab and nivolumab, have shown promising results in clinical trials for various cancers. Recent research has also indicated their potential benefit in fibrosis treatment in reducing fibroblast activation and extracellular matrix deposition, thereby addressing fibrosis. In this review, we examine the multifaceted role of PDL1 in immunomodulation, growth, and fibrosis promotion. We discuss the challenges, mechanisms, and clinical observations related to PDL1, including the limitations of the PD1/PDL1 axis in treatment and PD1-independent intrinsic PDL1 signaling. Our study highlights the dynamic changes in PDL1 expression during the EMT process across various tumor types. Through interplay between PDL1 and EMT, we uncover co-directional alterations, regulatory pathways, and diverse changes resulting from PDL1 intervention in oncology. Additionally, our findings emphasize the dual role of PDL1 in promoting fibrosis and modulating immune responses across multiple diseases, with potential implications for therapeutic approaches. We particularly investigate the therapeutic potential of targeting PDL1 in type II EMT fibrosis: strike balance between fibrosis modulation and immune response regulation. This analysis provides valuable insights into the multifaceted functions of PDL1 and contributes to our understanding of its complex mechanisms and therapeutic implications.

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The role of PD-1/PD-L1 axis in idiopathic pulmonary fibrosis: Friend or foe?

Cited by 8 publications

References 165 publications

Advancing the Boundaries of Immunotherapy in Lung Adenocarcinoma with Idiopathic Pulmonary Fibrosis by a Biomimetic Proteinoid Enabling Selective Endocytosis

Advancing the Boundaries of Immunotherapy in Lung Adenocarcinoma with Idiopathic Pulmonary Fibrosis by a Biomimetic Proteinoid Enabling Selective Endocytosis

The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases

What role does PDL1 play in EMT changes in tumors and fibrosis?

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