Trends in Molecular Medicine
ReviewThe two sides of HER2/neu: immune escape versus surveillance
Section snippets
HER2 as an important target for immunotherapy of cancer
In the era of personalized cancer medicine, the targeting of cancers that overexpress HER2 with the humanized monoclonal antibody (mAb) trastuzumab has become almost an iconic therapy for the treatment of solid tumors with remarkable clinical efficacy [1]. Major efforts to increase the clinical efficacy of HER antibodies are ongoing, including improved antibody efficacy through ‘antibody engineering’ and clever combinations with other therapies, either conventional or targeted 2, 3. However,
Characteristics of HER2
HER2 also termed HER2/neu, erbB2 or c-erbB2 is a 185-kDa transmembrane protein of the epidermal growth factor receptor (EGFR) family [9]. It comprises an extracellular, transmembrane, and intracellular domain with an intrinsic tyrosine kinase activity that can stimulate receptor-mediated signal transduction in the absence of ligand. HER2 forms heterodimers with other HER proteins, in particular with HER3 (Box 1). The response to HER2 activation depends on the given combination of HER proteins
HER2 can activate tumor-protective antibodies and T cells
BrCa, the prototype for a HER2 expressing tumor, is generally not regarded as immunogenic because spontaneous regressions have rarely if ever been described for this disease and in contrast to several other solid tumors no increased incidence of BrCa has been found in immunosuppressed patients [19]. These findings argue against BrCa being recognized by protective immune surveillance. Nevertheless, both humoral and cellular ‘spontaneous’ immunity to HER2 as well as several other cell surface and
Tumor cells can evade T cell mediated immune responses
A major prerequisite for a proper T cell response is the interaction between the T cell receptor (TCR) of CTLs with MHC class I antigens. Constitutive MHC class I surface expression requires a complex MHC class I antigen presentation machinery (APM) [24] and a process consisting of (i) peptide antigen generation and trimming mediated by the proteasome complex and aminopeptidases; (ii) the transport of these peptides from the cytosol into the endoplasmic reticulum via the heterodimeric
HER2-mediated transformation influences MHC class I APM expression and function
The expression and function of one or more APM components (TAP1 and TAP2 subunits, LMP2, LMP10, PA28, and/or tapasin) is downregulated in murine in vitro models of oncogenic transformation using, for example, RAS, MYC, MOS, and HER2. This downregulation was associated with low levels of MHC class I surface antigen expression and reduced CD8+ T cell recognition 28, 32, 33, 34, 35, 36, 37. Often, the APM-deficient phenotype could be reverted by gene transfer or by treatment with cytokines, such
The identification of the molecular mechanisms of HER2-mediated MHC class I downregulation will provide the basis for their restoration
To restore the expression of MHC class I APM components in HER2-transformed cells, a better knowledge of the underlying molecular mechanisms of APM deficiencies is required. The impaired expression of the different MHC class I APM components appears to a large extent to be mediated by deregulation, given that IFN-γ treatment can correct these defects in murine tumors and in some, but not all, human HER2-expressing tumor cells, as mentioned above (Figure 3; Box 2).
The HER2-mediated deregulation
HER2-mediated modulation of signal transduction in MHC class I APM deficiencies
HER2 signaling affects both the MAPK and PI3K/AKT signal transduction cascades (Figure 1), suggesting that these pathways modulate the expression of MHC class I APM components in vitro and in vivo. Indeed, blocking different steps of the MAPK pathway has been shown to enhance the expression of MHC class I APM components in some tumor cell lines of distinct origin. Although treatment with PD98059, a MAPK inhibitor, resulted in a dose-dependent upregulation of MHC class I surface expression in
Concluding remarks and implications for HER2-based immunotherapy of cancer
Different strategies exist to inhibit growth and/or eliminate HER2-expressing tumors (Box 2). Efforts to induce active immunity in cancer immunotherapy are almost exclusively focused on CTL-based therapies. As discussed above, CD8+ T cells and the adaptive immune system seem to be important, even for strategies involving the administration of a HER2-directed mAb such as trastuzumab. Consequently, suboptimal MHC class I expression as a result of oncogene-mediated downregulation has serious
References (69)
Efficacy of HER2-targeted therapy in metastatic breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors
Breast
(2013)The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity
Cancer Cell
(2010)Signal transduction and oncogenesis by ErbB/HER receptors
Int. J. Radiat. Oncol. Biol. Phys.
(2004)- et al.
Signaling through ERBB receptors: multiple layers of diversity and control
Cell. Signal.
(2006) Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance
Mod. Pathol.
(2012)Antigen-processing machinery breakdown and tumor growth
Immunol. Today
(2000)Defective human leukocyte antigen class I-associated antigen presentation caused by a novel β2-microglobulin loss-of-function in melanoma cells
J. Biol. Chem.
(2006)C-myc represses transiently transfected HLA class I promoter sequences not locus-specifically
Immunobiology
(1995)Identification of E2F1 as an important transcription factor for the regulation of tapasin expression
J. Biol. Chem.
(2010)Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2
Mol. Ther.
(2010)
CAR-T cells and solid tumors: tuning T cells to challenge an inveterate foe
Trends Mol. Med.
Cellular immunity to the Her-2/neu protooncogene
Adv. Cancer Res.
The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation
Trends Biochem. Sci.
Emerging targeted therapies for breast cancer
J. Clin. Oncol.
Superior in vivo efficacy of afucosylated trastuzumab in the treatment of HER2-amplified breast cancer
Cancer Res.
Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets
Nat. Med.
Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer
J. Clin. Oncol.
Elements related to heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab therapy for primary operable breast cancer overexpressing Her2
Cancer Res.
Augmented HER-2 specific immunity during treatment with trastuzumab and chemotherapy
Clin. Cancer Res.
EGFR family: structure physiology signalling and therapeutic targets
Growth Factors
Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues
Oncogene
Prognostic significance of HER2 and HER4 coexpression in childhood medulloblastoma
Cancer Res.
Expression of HER2/erbB-2 correlates with survival in osteosarcoma
J. Clin. Oncol.
Immunohistochemical expression of markers Ki-67, neun, synaptophysin, p53 and HER2 in medulloblastoma and its correlation with clinicopathological parameters
Arq. Neuropsiquiatr.
Low HER2-expressing glioblastomas are more often secondary to anaplastic transformation of low-grade glioma
J. Neurooncol.
HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells
Oncogene
Cancer incidence and risk factors after solid organ transplantation
Int. J. Cancer
Immune responses to all ErbB family receptors detectable in serum of cancer patients
Oncogene
Endogenous anti-HER2 antibodies block HER2 phosphorylation and signaling through extracellular signal-regulated kinase
Cancer Res.
Vaccination with a plasmid DNA encoding HER-2/neu together with low doses of GM-CSF and IL-2 in patients with metastatic breast carcinoma: a pilot clinical trial
J. Transl. Med.
Breast cancer vaccines: ongoing National Cancer Institute-registered clinical trials
Expert Rev. Vaccines
Recent advances in antigen processing and presentation
Nat. Immunol.
Regressing and progressing metastatic lesions: resistance to immunotherapy is predetermined by irreversible HLA class I antigen alterations
Cancer Immunol. Immunother.
‘Hard’ and ‘soft’ lesions underlying the HLA class I alterations in cancer cells: implications for immunotherapy
Int. J. Cancer
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2017, Cytokine and Growth Factor ReviewsCitation Excerpt :The altered tumor and immune cell metabolism caused hypoxia, a reduced pH, an increase of immune suppressive metabolites, e.g. indoleamine-2,3-dioxygenase (IDO), nitric oxide synthase (iNOS), arginase (ARG) and cytokines, like IL-10, transforming growth factor (TGF)-β and vascular endothelial growth factor (VEGF), which directly negatively interfere with the activity of immune effector cells as well as antigen presenting cells (APC). Furthermore, hypoxic conditions often present in the TME reduced anti-tumoral T cell responses [11–19]. Next to the interaction of immune cells with tumor cells, tumor cells can release immune suppressive exosomes, tumor-derived exosomes (TEX), which affect anti-tumor immune responses.
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