The Immune System's Contribution to the Clinical Efficacy of EGFR Antagonist Treatment

Macdonald, Felicity; Zaiss, Dietmar M.

doi:10.3389/fphar.2017.00575

Cited by 35 publications

(29 citation statements)

References 45 publications

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“…Instead it may be based on indirect effects, potentially mediated via the immune system. EGFR antagonist treatment could be impacting tumor growth by blocking macrophage and regulatory CD4+ T cell function (29).…”

Section: Discussionmentioning

confidence: 99%

Differential expression of egfr-1, mmp-3, and mmp-9 in spontaneous abortions, induced abortions, and tubal pregnancies

Balcı

Ozdemir²

2018

TJPATH

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Objective: The purpose of our study was to assess trophoblastic and uterine sufficiency in miscarriage pathogenesis with immunohistochemical methods and to determine if they could be used as a screening tool for the risk of miscarriage in the future. Material and Method: Placental tissue specimens that were comprised of 20 spontaneous abortions, 23 voluntarily terminated (induced) abortions, and 12 tubal pregnancies were included in this study. Trophoblastic cells and implantation area were evaluated for staining with EGFR-1, MMP-3, and MMP-9 by immunohistochemistry. Results: EGFR-1 expression was more intense and diffuse in decidual cells in the placental bed of spontaneous abortion specimens; this difference was statistically significant (P=0.004). MMP-3 expression was markedly increased in villous and extravillous trophoblastic cells in induced abortions; the difference between the groups was found to be statistically significant (P values ranged from < 0.01 to 0.005). MMP-9 expression tended to be higher in spontaneous abortion and tubal pregnancy specimens, and the results were statistically significant as P values were lower than 0.01. Conclusion: Higher EGFR-1 expression in the decidual tissue of spontaneous abortion specimens suggests that EGFR-1 triggers the migration of extravillous trophoblasts, leading to their destructive invasion. Similarly, MMP-9 immunopositivity might be indicative of aggressive invasion contributing to spontaneous abortion pathogenesis. Relatively high levels of MMP-3 expression in induced abortion specimens used as a control group might be a predictor of successful implantation, whereas its decreased expression might be indicative of risk for pregnancy loss.

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Section: Discussionmentioning

confidence: 99%

Differential expression of egfr-1, mmp-3, and mmp-9 in spontaneous abortions, induced abortions, and tubal pregnancies

Balcı

Ozdemir²

2018

TJPATH

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“…Several groups have already reported that EGFR mutational status has been correlated to PD-L1 expression [43][44][45]46]. In particular, Chen et al in their work demonstrated that EGFR activation by EGF stimulation, exon-19 deletions, and L858R mutation could induce PD-L1 expression through p-ERK1/2/p-c-Jun [46].…”

Section: Discussionmentioning

confidence: 98%

“…In this scenario another strategy under investigation is the combination of immune modulators and anti-EGFR therapy in a RAS WT population, elucidating the notion that the immune system substantially contributes to the therapeutic effects of monoclonal antibodies (moAbs) [43], NCT02713373, NCT03442569).…”

Section: Discussionmentioning

confidence: 99%

Triple blockade of EGFR, MEK and PD-L1 has antitumor activity in colorectal cancer models with constitutive activation of MAPK signaling and PD-L1 overexpression

Napolitano

Matrone

Muddassir

et al. 2019

J Exp Clin Cancer Res

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Background: Molecular mechanisms driving acquired resistance to anti-EGFR therapies in metastatic colorectal cancer (mCRC) are complex but generally involve the activation of the downstream RAS-RAF-MEK-MAPK pathway. Nevertheless, even if inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance, its use is limited by the development of MEK inhibitor (MEKi) resistance. Methods: We have generated in vitro and in vivo different CRC models in order to underline the mechanisms of MEKi resistance. Results: The three different in vitro MEKi resistant models, two generated by human CRC cells quadruple wild type for KRAS, NRAS, BRAF, PI3KCA genes (SW48-MR and LIM1215-MR) and one by human CRC cells harboring KRAS mutation (HCT116-MR) showed features related to the gene signature of colorectal cancer CMS4 with up-regulation of immune pathway as confirmed by microarray and western blot analysis. In particular, the MEKi phenotype was associated with the loss of epithelial features and acquisition of mesenchymal markers and morphology. The change in morphology was accompanied by up-regulation of PD-L1 expression and activation of EGFR and its downstream pathway, independently to RAS mutation status. To extend these in vitro findings, we have obtained mouse colon cancer MC38-and CT26-MEKi resistant syngeneic models (MC38-MR and CT26-MR). Combined treatment with MEKi, EGFR inhibitor (EGFRi) and PD-L1 inhibitor (PD-L1i) resulted in a marked inhibition of tumor growth in both models. Conclusions: These results suggest a strategy to potentially improve the efficacy of MEK inhibition by co-treatment with EGFR and PD-L1 inhibitors via modulation of host immune responses.

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“…More so, however intriguing the idea may be, it is pertinent to consider the associated challenges and drawbacks EGFR therapy might present. For instance, EGFR expression and function is crucial in all major immune cell types that include macrophages, T regs, dendritic cells, and so on and thus the administration of EGFR inhibitors or monoclonal antibodies to treat a particular pathology may render susceptibility to other pathologies and infections . It is known that Th2 responses are essential for controlling worm infections.…”

Section: Egfr‐directed Therapies For Persistent Infections: Future Pementioning

confidence: 89%

Immunological implications of epidermal growth factor receptor signaling in persistent infections

Mukherjee

Balaji

2019

IUBMB Life

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Infectious diseases account for a large proportion of global health emergencies and are rising more so owing to the paucity of effective vaccination and chemotherapeutic strategies. The severity is compounded by the development of antibiotic resistance among major pathogenic strains, capable of residing in the hostile host microenvironment by hijacking its signaling mechanisms and molecular circuitry. Among such processes, studies on epidermal growth factor receptor (EGFR) have revealed specific contributions of this classical oncogenic signaling axis during distinct infection conditions. Here, we review the current status of EGFR family members in the context of host-pathogen interactions and speculate the possible dimensions of exploration and manipulation of the EGFR pathway for host-directed therapeutic purposes. K E Y W O R D S epidermal growth factor receptor, host-directed therapeutics, immune responses, immunotherapy, mitochondrial/nuclear EGFR, persistent infections

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The Immune System's Contribution to the Clinical Efficacy of EGFR Antagonist Treatment

Cited by 35 publications

References 45 publications

Differential expression of egfr-1, mmp-3, and mmp-9 in spontaneous abortions, induced abortions, and tubal pregnancies

Differential expression of egfr-1, mmp-3, and mmp-9 in spontaneous abortions, induced abortions, and tubal pregnancies

Triple blockade of EGFR, MEK and PD-L1 has antitumor activity in colorectal cancer models with constitutive activation of MAPK signaling and PD-L1 overexpression

Immunological implications of epidermal growth factor receptor signaling in persistent infections

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