EGFR inhibitors, MHC expression and immune responses : Can EGFR inhibitors be used as immune response modifiers?

Pollack, Brian P.

doi:10.4161/onci.1.1.18073

Cited by 28 publications

(20 citation statements)

References 31 publications

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“…For example, it has recently been demonstrated that BRAF V600E inhibitors can increase the expression of MDAs, block the production of immunosuppressive cytokines such as IL-1α/β, and increase the recruitment of CD8 + T cells into tumors 17 , 37 , 38 . Indeed, it is becoming apparent that—in spite of the fact that the driving force behind the development of these therapeutic approaches had little to do with tumor immunology—the impact of targeted therapies on the expression of immune regulators may directly influence antitumor immune responses 39 . Our data also suggest that—in addition to providing a growth advantage to tumor cells—the genetic amplification of BRAF V600E may also promote tumor cell immune escape by attenuating the baseline expression levels of MHC Class I molecules.…”

Section: Discussionmentioning

confidence: 99%

Vemurafenib enhances MHC induction inBRAF^V600Ehomozygous melanoma cells

2013

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To optimally integrate targeted kinase inhibitors and immunotherapies in the treatment of melanoma, it will be critical to understand how BRAFV600E mutational status and BRAFV600E inhibition influence the expression of genes that govern antitumor immune responses. Because major histocompatibility complex (MHC) molecules are critical for interactions between tumor cells and lymphocytes, we investigated the impact of BRAFV600E-selective inhibitors on the expression of MHC molecules. We found that the treatment of A375 melanoma cells with vemurafenib enhances the induction of MHC Class I and Class II molecules by interferon γ and IFNα2b. Consistent with these findings, we observed that the forced overexpression of BRAFV600E has the opposite effect and can repress the baseline expression of MHC Class I molecules in A375 cells. Further studies utilizing eight other melanoma cell lines revealed that the vemurafenib-mediated enhancement of MHC induction by IFNγ only occurs in the context of homozygous, but not heterozygous, BRAFV600E mutation. These findings suggest that BRAFV600Eactivity directly influences the expression of MHC molecules and the response to Type I and Type II IFNs. Furthermore, our data suggest that the effect of vemurafenib on the expression of immune system-relevant genes may depend on the zygosity of the BRAFV600E mutation, which is not routinely assessed in melanoma patients.

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Section: Discussionmentioning

confidence: 99%

Vemurafenib enhances MHC induction inBRAF^V600Ehomozygous melanoma cells

2013

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“…ErbB receptors belong to a transmembrane tyrosine kinases receptor family that includes four members: the epidermal growth factor (EGF) receptor (EGFR; ErbB1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4) 15 . One possible mechanism that has been described to explain MHC‐I inhibition is the induction of the EGFR pathway 16 , 17 . This mechanism has been widely investigated in several infectious pathologies, autoimmunity and tumors 16 , 17 .…”

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Inhibition of MHC‐I by Brucella abortus is an early event during infection and involves EGFR pathway

et al. 2016

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Brucella abortus is able to persist inside the host despite the development of potent CD8 T-cell responses. We have recently reported the ability of B. abortus to inhibit the interferon-γ-induced major histocompatibility complex (MHC)-I cell surface expression on human monocytes. This phenomenon was due to the B. abortus-mediated retention of MHC-I molecules within the Golgi apparatus and was dependent on bacterial viability. However, the implications of bacterial virulence or replicative capacity and the signaling pathways remained unknown. Here we demonstrated that the B. abortus mutant strains RB51 and virB10 are able to inhibit MHC-I expression in the same manner as wild-type B. abortus, even though they are unable to persist inside human monocytes for a long period of time. Consistent with this, the phenomenon was triggered early in time and could be observed at 8 h postinfection. At 24 and 48 h, it was even stronger. Regarding the signaling pathway, targeting epidermal growth factor (EGF) receptor (EGFR), ErbB2 (HER2) or inhibition of tumor necrosis factor-α-converting enzyme, one of the enzymes which generates soluble EGF-like ligands, resulted in partial recovery of MHC-I surface expression. Moreover, recombinant EGF and transforming growth factor-α as well as the combination of both were also able to reproduce the B. abortus-induced MHC-I downmodulation. Finally, when infection was performed in the presence of an extracellular signal-regulated kinase 1/2 (Erk1/2) inhibitor, MHC-I surface expression was significantly recovered. Overall, these results describe how B. abortus evades CD8 T-cell responses early during infection and exploits the EGFR-ERK signaling pathway to escape from the immune system and favor chronicity.

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“…In immunocompromised mice xenografted with human tumors, this activity obviously reflects cancer cell-intrinsic (or stromal) mechanisms. As a matter of fact, mTORC1 is hyperactivated (hence delivering critical pro-survival signals) in a large number of malignancies, most often due to genetic or epigenetic alterations that result in constitutive signaling via upstream tyrosine kinase receptors (e.g., the epidermal growth factor receptor, EGFR) [64-67]. Conversely, the anticancer effects of rapalogs in immunocompetent settings appear to rely, at least in part, on the elicitation of tumor-targeting immune responses.…”

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confidence: 99%

Immunostimulatory activity of lifespan-extending agents

Pedro

Senovilla

2013

Aging

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During the past two decades, several interventions have been shown to increase the healthy lifespan of model organisms as evolutionarily distant from each other as yeast, worms, flies and mammals. These anti-aging maneuvers include (but are not limited to) cycles of caloric restriction, physical exercise as well as the administration of multiple, chemically unrelated agents, such as resveratrol, spermidine and various rapamycin-like compounds collectively known as rapalogs. Most, if not all, lifespan-extending agents promote macroautophagy (hereafter referred to as autophagy), an evolutionarily old mechanism that contributes to the maintenance of intracellular homeostasis and plays a critical role in the adaptive response of cells to stress. In line with this notion, the activation of autophagy appears to mediate significant anti-ageing effects in several organisms, including mice. Here, we focus on rapalogs to discuss the possibility that part of the beneficial activity of lifespan-extending agents stems from their ability to exert immunostimulatory effects. Accumulating evidence indicates indeed that the immune system can recognize and eliminate not only cells that are prone to undergo malignant transformation, but also senescent cells, thus playing a significant role in the control of organismal aging. In addition, it has recently become clear that rapamycin and other rapalogs, which for a long time have been viewed (and used in the clinic) as pure immunosuppressants, can mediate robust immunostimulatory functions, at least in some circumstances.

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EGFR inhibitors, MHC expression and immune responses : Can EGFR inhibitors be used as immune response modifiers?

Cited by 28 publications

References 31 publications

Vemurafenib enhances MHC induction inBRAF^V600Ehomozygous melanoma cells

Vemurafenib enhances MHC induction inBRAF^V600Ehomozygous melanoma cells

Inhibition of MHC‐I by Brucella abortus is an early event during infection and involves EGFR pathway

Immunostimulatory activity of lifespan-extending agents

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EGFR inhibitors, MHC expression and immune responses : Can EGFR inhibitors be used as immune response modifiers?

Cited by 28 publications

References 31 publications

Vemurafenib enhances MHC induction inBRAFV600Ehomozygous melanoma cells

Vemurafenib enhances MHC induction inBRAFV600Ehomozygous melanoma cells

Inhibition of MHC‐I by Brucella abortus is an early event during infection and involves EGFR pathway

Immunostimulatory activity of lifespan-extending agents

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Product

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Vemurafenib enhances MHC induction inBRAF^V600Ehomozygous melanoma cells

Vemurafenib enhances MHC induction inBRAF^V600Ehomozygous melanoma cells