EGFR-TKI down-regulates PD-L1 in EGFR mutant NSCLC through inhibiting NF-κB

Lin, Kailong; Cheng, Jianan; Yang, Tao; Li, Yongsheng; Zhu, Bo

doi:10.1016/j.bbrc.2015.05.030

Cited by 132 publications

(135 citation statements)

References 23 publications

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“…In addition, others have demonstrated that oncogenic alterations can induce PD-L1 expression. [48][49][50] The correlations we report between lymphocyte infiltration (in particular CD3 and CD8 C ) and distribution (immunotype) with PD-L1 expression, and the lack of any association with BRAF mutational status, suggest that PD-L1 expression by human melanoma cells can be explained predominantly by adaptive resistance. We only found a single case where PD-L1 expression was observed in greater than 5% of the tumor cells in the absence of any CD8 C T cells, a result consistent to Taube and colleagues' finding.…”

Section: Discussionmentioning

confidence: 66%

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

et al. 2016

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Therapeutic blockade of PD-1/PD-L1 can have dramatic therapeutic benefit in some patients; however, the prognostic associations of PD-1 and its ligands, in the absence of therapeutic blockade have not been definitively addressed. In particular, associations of PD-L2 with immune infiltrates and with outcome have yet to be explored. We hypothesized that surface expression of both PD-L1 and PD-L2 by melanoma cells would be associated with immune cell infiltration and with overall patient survival, independent of checkpoint blockade therapy. We also characterized the heterogeneity of their distribution within a tumor and within tumors of the same patient. Tissue microarrays of metastatic melanoma samples from 147 patients were quantified for CD8 C , CD45, CD4 C , CD3, CD163, CD20, CD138, FoxP3, PD-1, PD-L1 and PD-L2 markers by immunohistochemistry. Relationships between the proportions of PD-L1 and PD-L2 expressing tumor cells with the immune cell count, distribution (immunotype) and patient survival were studied. Expressions of both PD-L1 and PD-L2 correlated significantly with increasing densities of immune cells in the tumor specimens and with immunotype. Positive PD-L2 expression was associated with improved overall survival and the simultaneous positive expression of both PD-1 ligands showed a higher association with survival. Significant heterogeneity of PD-L1 and PD-L2 expressions within tumors were observed, however, they were less pronounced with PD-L2. In conclusion, both are markers of immune infiltration and PD-L2, alone or in combination with PD-L1, is a marker for prognosis in metastatic melanoma patients. Larger tumor samples yield more reliable assessments of PD-L1/L2 expression.

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Section: Discussionmentioning

confidence: 66%

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

et al. 2016

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“…EGFR mutants promote tumorigenesis of NSCLC by constitutively activating downstream signaling effectors, including PI3K/AKT, RAS/ERK, and others . Activated AKT, as a key downstream effector of the EGFR pathway, has been reported to activate NF‐κB and thereby regulate PD‐L1 expression . As an important transcription factor, NF‐κB transactivates PD‐L1 expression by binding directly to the PD‐L1 promoter .…”

Section: Discussionmentioning

confidence: 99%

“…30,31 Activated AKT, as a key downstream effector of the EGFR pathway, has been reported to activate NF-κB and thereby regulate PD-L1 expression. 32 As an important transcription factor, NF-κB transactivates PD-L1 expression by binding directly to the PD-L1 promoter. 33 Further flow cytometry analysis indicated that NSCLC cells with mutated EGFR showed clearly higher percentages of cells that were both EGFR and PD-L1 positive on the cell surface than the remaining NSCLC cell lines carrying WT EGFR.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia‐inducible factor‐1α and nuclear factor‐κB play important roles in regulating programmed cell death ligand 1 expression by epidermal growth factor receptor mutants in non‐small‐cell lung cancer cells

Guo

Wang

et al. 2019

Cancer Science

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Some driver gene mutations, including epidermal growth factor receptor ( EGFR ), have been reported to be involved in expression regulation of the immunosuppressive checkpoint protein programmed cell death ligand 1 ( PD ‐L1), but the underlying mechanism remains obscure. We investigated the potential role and precise mechanism of EGFR mutants in PD ‐L1 expression regulation in non‐small‐cell lung cancer ( NSCLC ) cells. Examination of pivotal EGFR signaling effectors in 8 NSCLC cell lines indicated apparent associations between PD ‐L1 overexpression and phosphorylation of AKT and ERK , especially with increased protein levels of phospho‐IκBα (p‐IκBα) and hypoxia‐inducible factor‐1α (HIF‐1α). Flow cytometry results showed stronger membrane co‐expression of EGFR and PD ‐L1 in NSCLC cells with EGFR mutants compared with cells carrying WT EGFR . Additionally, ectopic expression or depletion of EGFR mutants and treatment with EGFR pathway inhibitors targeting MEK / ERK , PI 3K/ AKT , mTOR /S6, IκBα, and HIF ‐1α indicated strong accordance among protein levels of PD ‐L1, p‐IκBα, and HIF ‐1α in NSCLC cells. Further treatment with pathway inhibitors significantly inhibited xenograft tumor growth and p‐IκBα, HIF ‐1α, and PD ‐L1 expression of NSCLC cells carrying EGFR mutant in nude mice. Moreover, immunohistochemical analysis revealed obviously increased protein levels of p‐IκBα, HIF ‐1α, and PD ‐L1 in NSCLC tissues with EGFR mutants compared with tissues carrying WT EGFR . Non‐small‐cell lung cancer tissues with either p‐IκBα or HIF ‐1α positive staining were more likely to possess elevated PD ‐L1 expression compared with tissues scored negative for both p‐IκBα and HIF ‐1α. Our findings showed important roles of phosphorylation activation of AKT and ERK and potential interplay and cooperation between NF ‐κB and HIF ‐1α in PD ‐L1 expression regulation by EGFR mutants in NSCLC .

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“…Previous study has reported that PD‐1 + and TIM‐3 + tumor‐infiltrating lymphocytes were increased after cetuximab therapy in HNSCC patients, and the increased frequency of PD‐1 + and TIM‐3 + TILs was inversely correlated with clinical outcome of cetuximab therapy . Gefitinib, an EGFR‐tyrosine kinase inhibitors (TKIs), could cause a substantial PD‐L1 reduction in non‐small cell lung cancer but is upregulated in the patients who are acquired resistance to it . Moreover, higher PD‐L1 was more likely occurred in the tumors with EGFR‐mutated than those without .…”

Section: Discussionmentioning

confidence: 99%

Altered expression of TIM‐3, LAG‐3, IDO, PD‐L1, and CTLA‐4 during nimotuzumab therapy correlates with responses and prognosis of oral squamous cell carcinoma patients

Wang

Mao

Zhang

et al. 2019

J Oral Pathology Medicine

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Background Since the inhibitory immune checkpoint receptors have been described to benefit the OSCC patients clinically, it is unknown that whether their expression in tumor immune microenvironment (TME) can determine the clinical outcome in response to nimotuzumab therapy. Methods We examined the expression patterns of immune checkpoint receptors (including TIM‐3, LAG‐3, PD‐L1, and CTLA‐4) and an immunoregulatory enzyme called IDO in 36 OSCC patients during nimotuzumab therapy by immunohistochemistry. Then, we divided the recruited patients into clinical responders and non‐responders according to computed tomography (CT) scan and analyzed the relationship between the immunological parameters and clinical outcome. Results We observed that nimotuzumab therapy significantly increased the expression of TIM‐3, LAG‐3, IDO, PD‐L1, and CTLA‐4 in the TME, and the expression of LAG‐3 and PD‐L1 before nimotuzumab therapy was inversely correlated with the overall survival. In clinical non‐responders, we found the expression of TIM‐3, LAG‐3, IDO, PD‐L1, and CTLA‐4 was significantly increased during nimotuzumab therapy, and the expression of TIM‐3, LAG‐3, IDO, PD‐L1, and CTLA‐4 before nimotuzumab therapy was negatively correlated with the overall survival. However, in clinical responders, neither of those showed significant. Conclusions It suggests that these immune checkpoint receptors and IDO could be considered as biomarkers to reflect immune status in the tumor microenvironment during nimotuzumab therapy. Blockade of these immune checkpoint receptors might enhance nimotuzumab‐based cancer immunotherapy, thus potentially improving clinical outcomes of OSCC patients.

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EGFR-TKI down-regulates PD-L1 in EGFR mutant NSCLC through inhibiting NF-κB

Cited by 132 publications

References 23 publications

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

Hypoxia‐inducible factor‐1α and nuclear factor‐κB play important roles in regulating programmed cell death ligand 1 expression by epidermal growth factor receptor mutants in non‐small‐cell lung cancer cells

Altered expression of TIM‐3, LAG‐3, IDO, PD‐L1, and CTLA‐4 during nimotuzumab therapy correlates with responses and prognosis of oral squamous cell carcinoma patients

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