Expression of MHC Class I on breast cancer cells correlates inversely with HER2 expression

Abstract

HER2 is a promising target for immunotherapeutic interventions with T cell-based approaches since it is amplified and overexpressed in 20–30% of breast cancers. However, several previous studies including ours showed that HER2-overexpressing tumors may escape cytotoxic T lymphocyte-mediated lysis by downregulating MHC Class I and components of the antigen-processing machinery. The aims of the present study were to analyze the relationship between HER2 and MHC Class I expression and to elucidate the mechanisms underlying MHC Class I downregulation in breast cancer. We explored expression of HER2, MHC Class I, PTEN, Ki67, estrogen and progesterone expression in 70 breast cancer patients by immunohistochemistry (IHC) and analyzed their correlation. We also explored the components of the signal transduction pathway that are involved in the regulation of MHC Class I expression using small-interfering RNAs targeting HER2 as well as an inhibitor of HER2 signaling. HER2 expression in breast cancers correlated inversely with MHC Class I expression analyzed by IHC. HER2 depletion by small-interfering RNAs resulted in MHC Class I upregulation. Moreover, MHC Class I expression on breast cancer cell lines was upregulated by PD98059, an inhibitor of mitogen-associated protein kinases, in a dose-dependent manner. Thus, agents that target the MAPK signaling pathway may increase MHC Class I expression in breast cancer cells.

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

“…Possible reasons for the difference in results between our study and previous studies could be differences in the cell types and the HER2 sequences targeted by siRNA. [20][21][22] In our study, we found that treatment of the cells with siRNA#1, which knocked down HER2 and increased expression of HLA-ABC, also upregulated expression of STAT1, a known major transcription factor regulating HLA-ABC expression. 27 However, we did not find STAT1 upregulation following treatment with any of the other four siRNAs, suggesting a possible off-target effect of siRNA#1.…”

“…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.…”

“…18 A few early studies reported an inverse correlation between HER2 level and HLA-ABC expression in some breast cancer cell lines. [20][21][22] Also playing a role in T cell activation are the CD80 and CD86 T cell costimulatory molecules, which provide second signals necessary for T cell activation and survival through binding to CD28 on the T cell surface and also binding to CTLA-4 for attenuation of the regulation. Expression of CD80 and CD86 is found not only in antigen-presenting cells but also in some human cancer cell lines.…”

A Therapeutic Her2/neu Vaccine Targeting Dendritic Cells Preferentially Inhibits the Growth of Low Her2/neu–Expressing Tumor in HLA-A2 Transgenic Mice

“…These results could be explained by the interference of Her2/neu with T-cell recognition via an inhibition of HLA class I molecules mediated by an activation of the MAPK pathway (40,41). An inverse correlation between Her2/neu and MHC class I antigenprocessing machinery (APM) component levels in human mammary carcinoma lesions has also been reported supporting this hypothesis (41).…”

The non-inflammatory role of C1q during Her2/neu-driven mammary carcinogenesis

“…45 NeuT C tumor cells are susceptible to the activity of NK cells, as an inverse correlation exists between the expression levels of neuT protein and those of MHC class I molecules as well as other components of the antigen-processing machinery. 46 Moreover, signaling through the Her2/Her3 pathway in breast tumor cell lines has been shown to enhance their recognition by NK and T cells thanks to the killer cell lectin-like receptor subfamily K, member 1 (KLRK1, or NKG2D). 47 In conclusion, our data demonstrate that the C1q protein protects against the development of Her2/neu C mammary carcinomas, at least in our preclinical BALB-neuT female mouse model.…”