The TLR4/ERK/PD‑L1 axis may contribute to NSCLC initiation

Kang, Xiuhua; Li, Penghui; Zhang, Chuibin; Yun-feng, Zhao; Hu, Huoli; Wen, Ge

doi:10.3892/ijo.2020.5068

Cited by 25 publications

(19 citation statements)

References 48 publications

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“…Both IFN-γ- and LPS-induced PD-L1 expression on tumor-infiltrating macrophages is dependent on the activation of STAT3 ( 51 , 52 ). Moreover, activation of the TLR4/ERK axis is responsible for LPS-induced PD-L1 expression ( 53 ). In addition to CSF1/CSF1R blockade, macrophage reprogramming using HDAC inhibitors or agonistic anti-CD40 antibodies increases the expression of PD-L1 on macrophages, which limits the anti-tumor effect of reprogrammed TAMs ( 54 , 55 ).…”

Section: M2 To M1 Reprogramming Is Associated With Increased Pd-l1 Expressionmentioning

confidence: 99%

Defects in Macrophage Reprogramming in Cancer Therapy: The Negative Impact of PD-L1/PD-1

et al. 2021

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Classically activated M1 macrophages and alternatively activated M2 macrophages are two polarized subsets of macrophages at the extreme ends of a constructed continuum. In the field of cancer research, M2 macrophage reprogramming is defined as the repolarization of pro-tumoral M2 to anti-tumoral M1 macrophages. It is known that colony-stimulating factor 1 (CSF1)/CSF1 receptor (CSF1R) and CSF2/CSF2R signaling play important roles in macrophage polarization. Targeting CSF1/CSF1R for M2 macrophage reprogramming has been widely performed in clinical trials for cancer therapy. Other targets for M2 macrophage reprogramming include Toll-like receptor 7 (TLR7), TLR8, TLR9, CD40, histone deacetylase (HDAC), and PI3Kγ. Although macrophages are involved in innate and adaptive immune responses, M1 macrophages are less effective at phagocytosis and antigen presenting, which are required properties for the activation of T cells and eradication of cancer cells. Similar to T and dendritic cells, the “functionally exhausted” status might be attributed to the high expression of programmed death-ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1). PD-L1 is expressed on both M1 and M2 macrophages. Macrophage reprogramming from M2 to M1 might increase the expression of PD-L1, which can be transcriptionally activated by STAT3. Macrophage reprogramming or PD-L1/PD-1 blockade alone is less effective in the treatment of most cancers. Since PD-L1/PD-1 blockade could make up for the defect in macrophage reprogramming, the combination of macrophage reprogramming and PD-L1/PD-1 blockade might be a novel treatment strategy for cancer therapy.

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Section: M2 To M1 Reprogramming Is Associated With Increased Pd-l1 Expressionmentioning

confidence: 99%

Defects in Macrophage Reprogramming in Cancer Therapy: The Negative Impact of PD-L1/PD-1

et al. 2021

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“…Consistent with prior study, PD-L1 overexpression or knockout affects the proliferation and migration of cancer cells through Erk signaling pathway [36] . Meanwhile, MAPK/ERK signaling pathway can affect the expression of PD-L1 [37,38] . Therefore, these ndings indicate that combination of apatinib and PD-L1 inhibitor can inhibit cell proliferation, reduce migration and invasion ,increase apoptisis possibly by attenuating the expression of p-Erk/NF-κB/Slug in breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

The synergistic anticancer effects of apatinib combined with PD-L1 inhibitor on breast cancer

Han

et al. 2022

Preprint

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Purpose: Apatinib have potential anti-angiogenic and anti-tumor activities in breast cancer. PD-L1 inhibitor also has a good effect on breast cancer . In this study we aimed to discuss the synergistic effect of apatinib combined with PD-L1 inhibitor and explore its mechanisms in breast cancer. Method: We investigated the synergistic effects of apatinib and PD-L1 inhibitor on breast cancer in vitro and in vivo. MTT assay, Wound-healing, and transwell invasion assays were used to determine the effects of apatinib and PD-L1 inhibitor on cell proliferation, migration, and invasion of MCF-7 and MDA-MB-231 cells in vitro. Western blotting was performed to assess the expression of Erk, p-Erk, NF-κB and slug. In vivo, xenograft model were established to test the effect of single drug or the combined therapy in the nude mice.Results: The results indicated that apatinib and PD-L1 inhibitor significantly inhibit proliferation, migration and invasion of MCF-7 and MDA-MB-231 cells. The combined treatment showed synergistic anticancer activities. Moreover, apatinib and PD-L1 inhibitor significantly downregulated the expression of p-Erk, NF-κB and slug in breast cancer cells. Conclusion: Apatinib and PD-L1 inhibitor show synergistic effects both in vitro and in vivo,which may provide a more effective treatment option for breast cancer patients.

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“…Triggering of the pathway causes exhaustion of effector T cell and immune escape ( 136 , 137 ). Studies also suggest that the expression of TLR4 and PD-L1 can indicate the prognosis of NSCLC, while TLR4 may increase expression of PD-L1 via the ERK signaling pathway ( 138 ). Systemic immune-inflammation index (SII) was found related to poor survival of NSCLC, the prognostic role of which was presented among NSCLC patients with solid nodules, adenocarcinoma, and stage I disease ( 139 ).…”

Section: Inflammation In Nsclc and Immune Component Of Inflammationmentioning

confidence: 99%

Epigenetic Alterations and Inflammation as Emerging Use for the Advancement of Treatment in Non-Small Cell Lung Cancer

Yang

Huang

Zhao³

2022

Front. Immunol.

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Lung cancer remains one of the most common malignancies in the world. Nowadays, the most common lung cancer is non-small cell lung cancer (NSCLC), namely, adenocarcinoma, squamous cell carcinoma, and large cell lung carcinoma. Epigenetic alterations that refer to DNA methylation, histone modifications, and noncoding RNA expression, are now suggested to drive the genesis and development of NSCLC. Additionally, inflammation-related tumorigenesis also plays a vital role in cancer research and efforts have been attempted to reverse such condition. During the occurrence and development of inflammatory diseases, the immune component of inflammation may cause epigenetic changes, but it is not always certain whether the immune component itself or the stimulated host cells cause epigenetic changes. Moreover, the links between epigenetic alterations and cancer-related inflammation and their influences on the human cancer are not clear so far. Therefore, the connection between epigenetic drivers, inflammation, and NSCLC will be summarized. Investigation on such topic is most likely to shed light on the molecular and immunological mechanisms of epigenetic and inflammatory factors and promote the application of epigenetics in the innovative diagnostic and therapeutic strategies for NSCLC.

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The TLR4/ERK/PD‑L1 axis may contribute to NSCLC initiation

Cited by 25 publications

References 48 publications

Defects in Macrophage Reprogramming in Cancer Therapy: The Negative Impact of PD-L1/PD-1

Defects in Macrophage Reprogramming in Cancer Therapy: The Negative Impact of PD-L1/PD-1

The synergistic anticancer effects of apatinib combined with PD-L1 inhibitor on breast cancer

Epigenetic Alterations and Inflammation as Emerging Use for the Advancement of Treatment in Non-Small Cell Lung Cancer

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