Inverse correlation of HER2 with MHC class I expression on oesophageal squamous cell carcinoma

Maruyama, Takanori; Mimura, Kousaku; Sato, Eiji; Watanabe, Masashi; Matsuo, Yoshiki; Kawaguchi, Yoshihiko; Ando, Tetsu; Kinouchi, Hiroyuki; Fujii, Hideki; Kono, Koji

doi:10.1038/sj.bjc.6605772

Cited by 35 publications

(24 citation statements)

References 34 publications

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“…In our previous studies, we showed that HER2 expression correlated inversely with HLA class I expression in breast cancer, ESCC, and melanoma (13,14), and silencing of HER2 resulted in upregulation of HLA class I in vitro (11,14). However, the upregulation of HLA class I by HER2 silencing was relatively marginal in comparison with that induced by MAPK inhibition in the current study.…”

Section: Discussionmentioning

confidence: 44%

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The MAPK Pathway Is a Predominant Regulator of HLA-A Expression in Esophageal and Gastric Cancer

Mimura

Shiraishi

Müeller

et al. 2013

The Journal of Immunology

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Downregulation of HLA class I expression may contribute to a poor prognosis in cancer patients. There is limited information about epigenetic and oncogenic regulation of HLA class I, and multiple mechanisms may be involved. In the current study, we examined the relationship between the HER2-signaling pathway (MAPK and PI3K-Akt) and the expression of HLA class I and Ag-processing machinery (APM) components. A panel of gastric and esophageal cancer cell lines was treated with wortmannin as an Akt-signal inhibitor; the MAPK signal inhibitor PD98059; lapatinib, which inhibits both the epidermal growth factor receptor and HER2 tyrosine kinase; or siRNA for MAPK. The levels of HER2-signaling molecules, APM components, and HLA class I were evaluated by Western blot, quantitative PCR, and flow cytometry. Resected gastric tumor tissues (n = 102) were analyzed for p-Erk and HLA class I expression by immunohistochemistry. As a result, inhibition of the MAPK pathway induced upregulation of HLA-A02 and HLA-A24 expression in parallel with an increase in APM components and enhanced target sensitivity to tumor Ag–specific CTL lysis. HLA-A expression was predominantly regulated by the MAPK pathway, but it was also influenced, in part, by the Akt pathway. There was a strong inverse correlation between p-Erk expression and HLA class I expression in clinical tumor samples. In conclusion, HLA-A expression is predominantly regulated by the MAPK pathway in gastric and esophageal cancer.

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Section: Discussionmentioning

confidence: 44%

“…In addition, we reported that the downregulation of HER2 with small interfering RNA (siRNA) technology on ESCC resulted in increased expression of HLA class I (11,14). These observations strongly indicated that HER2 signaling is closely related to the regulation of HLA class I expression.…”

mentioning

confidence: 61%

The MAPK Pathway Is a Predominant Regulator of HLA-A Expression in Esophageal and Gastric Cancer

Mimura

Shiraishi

Müeller

et al. 2013

The Journal of Immunology

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“…It has been proposed that over‐expression of the oncogene HER‐2/neu down‐regulates the expressions of APM components and MHC‐I 53–56. Bianchi et al reported that Fhit protein levels can be regulated in breast and ovarian cancer cell lines expressing Fhit and over‐expressing EGFR and HER2 by Fhit proteasome degradation mediated by the EGF‐dependent activation of EGFR family members 57, 58.…”

Section: Discussionmentioning

confidence: 99%

The tumour suppressor Fhit positively regulates MHC class I expression on cancer cells

Romero

Martínez²,

Garrido

et al. 2012

The Journal of Pathology

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MHC class I (MHC‐I) molecules are ubiquitously expressed on the cells of an organism. Study of the regulation of these molecules in normal and disease conditions is important. In tumour cells, the expression of MHC‐I molecules is very frequently lost, allowing these cells to evade the immune response. Cancers of different histology have shown total loss of MHC‐I molecule expression, due to a coordinated transcriptional down‐regulation of various antigen‐processing machinery (APM) components and/or MHC‐I heavy chains. The mechanisms responsible for these alterations remain unclear. We determined the possible genes involved by comparing MHC‐I‐positive with MHC‐I‐negative murine metastases derived from the same fibrosarcoma tumour clone. MHC‐I‐negative metastases showed transcriptional down‐regulation of APM and MHC‐I heavy chains. The use of microarrays and subtraction cDNA libraries revealed four candidate genes responsible for this alteration, but two of them were ruled out by real‐time RT‐PCR analyses. The other two genes, AP‐2α and Fhit tumour suppressors, were studied by using siRNA to silence their expression in a MHC‐I‐positive metastatic cell line. AP‐2α inhibition did not modify transcriptional expression of APM components or MHC‐I heavy chains or surface expression of MHC‐I. In contrast, silencing of the Fhit gene produced the transcriptional down‐regulation of APM components and MHC‐I heavy chains and decreased MHC‐I surface expression. Moreover, transfection of Fhit in MHC‐I‐negative tumour cell lines restored MHC‐I cell surface expression. These data indicate that defects in Fhit expression may promote MHC‐I down‐regulation in cancer cells and allow escape from immunosurveillance#. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…A few earlier studies showed that HER2 regulates the components of the MHC class I antigen processing machinery and showed that there was an inverse correlation between HER2 and HLA-ABC expression following siRNA-mediated knockdown of HER2 expression in some breast cancer cell lines (SKBR3 and MCF7-HER2) and some non-breast cancer cell lines. [20][21][22]33,34 In our study, we examined the effect of HER2 knockdown in five HER2-overexpressing cell lines using five different siRNAs. We did not find a significant inverse correlation between the levels of expression of HER2 and HLA-ABC except with one particular siRNA.…”

Section: Discussionmentioning

confidence: 99%

Trastuzumab upregulates expression of HLA-ABC and T cell costimulatory molecules through engagement of natural killer cells and stimulation of IFNγ secretion

et al. 2015

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It is increasingly recognized that trastuzumab, an antibody approved for treating human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer, exerts some of its antitumor effects through enhanced T cell responses. Full activation of CD8 C T cells requires both expression of major histocompatibility complex class I molecules (HLA-ABC) and expression of the T cell costimulatory molecule CD80 or CD86; however, the impact of trastuzumab treatment on the expression of HLA-ABC and CD80 and CD86 has not been investigated in HER2-overexpressing breast cancer cells. In this study, we found that, while there is no direct correlation between the expression of HER2 and HLA-ABC in breast cancer, knockdown of HER2 or inhibition of HER2 kinase by lapatinib downregulated HLA-ABC expression. Trastuzumab had no meaningful effects on HLA-ABC expression in HER2-overexpressing breast cancer cells in monoculture; however, treatment of such cells with trastuzumab in co-culture with human peripheral blood mononuclear cells (PBMC) significantly upregulated not only HLA-ABC expression but also CD86 expression. We showed that this upregulation was mediated by interferon gamma (IFNg) secreted from the natural killer (NK) cells in PBMC as a result of engagement of NK cells by trastuzumab. We further confirmed this effect of trastuzumab in vivo using a mouse mammary tumor model transduced to overexpress human HER2. Together, our data provide evidence that trastuzumab upregulates expression of HLA-ABC and T cell costimulatory molecules in HER2-overexpressing breast cancer cells in the presence of PBMC, which supports the view that T-cell-mediated immune responses are involved in trastuzumab-mediated antitumor effects.

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Inverse correlation of HER2 with MHC class I expression on oesophageal squamous cell carcinoma

Cited by 35 publications

References 34 publications

The MAPK Pathway Is a Predominant Regulator of HLA-A Expression in Esophageal and Gastric Cancer

The MAPK Pathway Is a Predominant Regulator of HLA-A Expression in Esophageal and Gastric Cancer

The tumour suppressor Fhit positively regulates MHC class I expression on cancer cells

Trastuzumab upregulates expression of HLA-ABC and T cell costimulatory molecules through engagement of natural killer cells and stimulation of IFNγ secretion

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