Crosstalk between the B7/CD28 and EGFR pathways: Mechanisms and therapeutic opportunities

Ren, Xiaoxin; Li, Yixian; Nishimura, Christopher; Zang, Xingxing

doi:10.1016/j.gendis.2021.08.009

Cited by 11 publications

(5 citation statements)

References 157 publications

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“…Therefore, targeting EGFR with the small molecule gefitinib markedly increased the response to chemotherapy in B7-H3-overexpressing CRC in vitro and in vivo. A previous study reported that B7-H3-induced signaling shares a similar signaling pathway with EGFR, which supports our results [49]. Ding et al indicated that the B7-H3-induced signaling pathway activated the divergent EGFR signaling pathway, suggesting the translational potential of combined targeted therapy of B7-H3 and EGFR in non-small lung adenocarcinoma [39].…”

Section: Discussionsupporting

confidence: 91%

Dual Inhibition of B7-H3 and EGFR Overcomes Acquired Chemoresistance in Colon Adenocarcinoma

Chen,

Yang,

Chen

et al. 2024

J. Cancer

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Despite advances in therapeutic strategies for colorectal cancer (CRC), CRC has a high disease incidence with significant morbidity and mortality worldwide. Notably, immunotherapy has shown limited efficacy in treating metastatic CRC, underscoring the need for alternative immunotherapeutic targets for the management of metastatic colorectal cancer (mCRC). In the present study, we evaluated the levels of the immune checkpoint proteins PD-L1, PD-L2 and B7-H3 in a large cohort retrospective study. We found that tumor B7-H3 (52.7%) was highly expressed in primary tumors compared to that in PD-L1 (33.6%) or PD-L2 (34.0%). Elevated B7-H3 expression was associated with advanced stage and the risk of distant metastasis and correlated with poor disease-free survival (DFS), suggesting that tumor B7-H3 was an independent prognostic factor associated with worse DFS in colon adenocarcinoma patients (COAD), especially high-risk COAD patients who received adjuvant chemotherapy. Furthermore, we found that B7-H3 significantly promoted cell proliferation and tumor growth in CRC. B7-H3 may stabilize EGFR to activate its downstream pathway for cancer cell proliferation and resistance to oxaliplatin (OXP). Dual targeting of B7-H3 and EGFR markedly rescued the susceptibility to chemotherapy in colorectal cancer cells in vitro and in vivo. Overall, these results showed that B7-H3 exhibited a high prevalence in COAD patients and was significantly associated with worse prognosis in COAD patients. Dual targeting of B7-H3 and EGFR signaling might be a potential therapeutic strategy for high-risk COAD patients.

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Section: Discussionsupporting

confidence: 91%

Dual Inhibition of B7-H3 and EGFR Overcomes Acquired Chemoresistance in Colon Adenocarcinoma

Chen,

Yang,

Chen

et al. 2024

J. Cancer

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“…Investigating the molecular pathways and mechanisms that facilitate interaction between CAFs and tumor cells during radiotherapy is crucial for enhancing clinical outcomes in patients with NSCLC [ 36 ]. This knowledge is foundational for developing targeted therapies to augment the efficacy of radiotherapy in NSCLC, ultimately aiming to improve patient prognosis [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Single-cell transcriptomic sequencing data reveal aberrant DNA methylation in SMAD3 promoter region in tumor-associated fibroblasts affecting molecular mechanism of radiosensitivity in non-small cell lung cancer

Han,

Chen,

Zhang

et al. 2024

J Transl Med

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Objective Non-small cell lung cancer (NSCLC) often exhibits resistance to radiotherapy, posing significant treatment challenges. This study investigates the role of SMAD3 in NSCLC, focusing on its potential in influencing radiosensitivity via the ITGA6/PI3K/Akt pathway. Methods The study utilized gene expression data from the GEO database to identify differentially expressed genes related to radiotherapy resistance in NSCLC. Using the GSE37745 dataset, prognostic genes were identified through Cox regression and survival analysis. Functional roles of target genes were explored using Gene Set Enrichment Analysis (GSEA) and co-expression analyses. Gene promoter methylation levels were assessed using databases like UALCAN, DNMIVD, and UCSC Xena, while the TISCH database provided insights into the correlation between target genes and CAFs. Experiments included RT-qPCR, Western blot, and immunohistochemistry on NSCLC patient samples, in vitro studies on isolated CAFs cells, and in vivo nude mouse tumor models. Results Fifteen key genes associated with radiotherapy resistance in NSCLC cells were identified. SMAD3 was recognized as an independent prognostic factor for NSCLC, linked to poor patient outcomes. High expression of SMAD3 was correlated with low DNA methylation in its promoter region and was enriched in CAFs. In vitro and in vivo experiments confirmed that SMAD3 promotes radiotherapy resistance by activating the ITGA6/PI3K/Akt signaling pathway. Conclusion High expression of SMAD3 in NSCLC tissues, cells, and CAFs is closely associated with poor prognosis and increased radiotherapy resistance. SMAD3 is likely to enhance radiotherapy resistance in NSCLC cells by activating the ITGA6/PI3K/Akt signaling pathway.

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“…The overexpression of PD-L1 and CD80/CD86 on tumor cells, which can respectively bind to PD-1 and cytotoxic T lymphocyte antigen 4 (CTLA4), results in the inhibition of T cell activation. Furthermore, recent research has also described a significant interaction between the PD-1/PD-L1 axis and the EGFR pathway [ 28 ]. These mechanisms ultimately help the tumor to escape anti-tumor immunity [ 3 , 4 , 5 , 28 , 29 , 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, recent research has also described a significant interaction between the PD-1/PD-L1 axis and the EGFR pathway [ 28 ]. These mechanisms ultimately help the tumor to escape anti-tumor immunity [ 3 , 4 , 5 , 28 , 29 , 30 , 31 ]. Therefore, monoclonal antibodies have been developed to antagonize this inhibitory signaling, and in the last decade, several randomized clinical trials have investigated the efficacy and safety of immune checkpoint inhibitors, including anti-PD-1 and anti-PD-L1 drugs [ 29 , 30 , 31 , 32 , 33 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

Does Elevated Pre-Treatment Plasma PD-L1 Level Indicate an Increased Tumor Burden and Worse Prognosis in Metastatic Colorectal Cancer?

Dank

Mühl

Herold

et al. 2022

JCM

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Background: Programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) have been reported as possibly favorable prognostic factors in colorectal cancer (CRC). However, their longitudinal effect is unknown. Methods: A pilot study was performed to investigate whether baseline PD-1/PD-L1 levels are associated with further laboratory changes and/or shorter survival. Results: A total of 506 laboratory measurements from 37 metastatic CRC patients were analyzed. The baseline plasma PD-1 and PD-L1 levels were 27.73 ± 1.20 pg/mL and 16.01 ± 1.09 pg/mL, respectively. Disease progression (p = 0.0443) and baseline high-sensitivity C-reactive protein (p = 0.0011), aspartate transaminase (p = 0.0253), alanine transaminase (p = 0.0386), and gamma-glutamyl transferase (p = 0.0103) were associated with higher PD-L1 levels. Based on the baseline PD-1/PD-L1 levels, low and high PD-1/PD-L1 groups were created. Constant, pathological levels of complete blood count values, high-sensitivity C-reactive protein, serum albumin, high-density lipoprotein cholesterol, and lactate dehydrogenase were characteristic for patients with high baseline PD-L1. High PD-L1 levels were significantly associated with increased tumor burden. Disease-specific survival and progression-free survival were significantly shorter in patients with high PD-L1. Conclusions: Abnormal levels of laboratory parameters and intensified tumor burden can be expected if elevated baseline plasma PD-1/PD-L1 levels are found.

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Crosstalk between the B7/CD28 and EGFR pathways: Mechanisms and therapeutic opportunities

Cited by 11 publications

References 157 publications

Dual Inhibition of B7-H3 and EGFR Overcomes Acquired Chemoresistance in Colon Adenocarcinoma

Dual Inhibition of B7-H3 and EGFR Overcomes Acquired Chemoresistance in Colon Adenocarcinoma

Single-cell transcriptomic sequencing data reveal aberrant DNA methylation in SMAD3 promoter region in tumor-associated fibroblasts affecting molecular mechanism of radiosensitivity in non-small cell lung cancer

Does Elevated Pre-Treatment Plasma PD-L1 Level Indicate an Increased Tumor Burden and Worse Prognosis in Metastatic Colorectal Cancer?

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