HER2/HER3 signaling regulates NK cell-mediated cytotoxicity via MHC class I chain-related molecule A and B expression in human breast cancer cell lines.

Abstract

Overexpression of the receptor tyrosine kinases HER2 and HER3 is associated with a poor prognosis in several types of cancer. Presently, HER2- as well as HER3-targeted therapies are in clinical practice or evaluated within clinical trials, including treatment with mAbs mediating growth inhibition and/or activation of Ab-induced innate or adaptive cellular immunity. A better understanding of how HER2/HER3 signaling in tumors influences cellular immune mechanisms is therefore warranted. In this study, we demonstrate that HER2/HER3 signaling regulates the expression of MHC class I-related chain A and B (MICA and MICB) in breast cancer cell lines. The MICA and MICB (MICA/B) molecules act as key ligands for the activating receptor NK group 2, member D (NKG2D) and promote NK cell-mediated recognition and cytolysis. Genetic silencing of HER3 but not HER2 downregulated the expression of MICA/B, and HER3 overexpression significantly enhanced MICA expression. Among the major pathways activated by HER2/HER3 signaling, the PI3K/AKT pathway was shown to predominantly regulate MICA/B expression. Treatment with the HER3-specific ligand neuregulin 1β promoted the expression in a process that was antagonized by pharmacological and genetic interference with HER3 but not by the ataxia-telangiectasia-mutated (ATM) and ATM and Rad3-related protein kinases inhibitor caffeine. These observations further emphasize that HER2/HER3 signaling directly, and not via genotoxic stress, regulates MICA/B expression. As anticipated, stimulating HER2/HER3 enhanced the NKG2D-MICA/B-dependent NK cell-mediated cytotoxicity. Taken together, we conclude that signaling via the HER2/HER3 pathway in breast carcinoma cell lines may lead to enhanced NKG2D-MICA/B recognition by NK cells and T cells.

• Authors: Riki Okita, Dimitrios Mougiakakos, Takashi Ando, Yumeng Mao, Dhifaf Sarhan, Erik Wennerberg, Barbara Seliger, Andreas Lundqvist, Kousaku Mimura, Rolf Kiessling
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 188 Issue 5 Pg. 2136-45 (Mar 01 2012) ISSN: 1550-6606 [Electronic] United States
• PMID: 22301547 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histocompatibility Antigens Class I
• MHC class I-related chain A
• MICB antigen
• ERBB2 protein, human
• Receptor, ErbB-2
• Receptor, ErbB-3

Topics

• Breast Neoplasms (enzymology, genetics, immunology)
• Cell Line, Tumor
• Cytotoxicity Tests, Immunologic (methods)
• Female
• Gene Expression Regulation, Neoplastic (immunology)
• Histocompatibility Antigens Class I (biosynthesis, genetics)
• Humans
• Killer Cells, Natural (immunology, metabolism, pathology)
• MAP Kinase Signaling System (immunology)
• Receptor, ErbB-2 (biosynthesis, physiology)
• Receptor, ErbB-3 (biosynthesis, physiology)
• Signal Transduction (genetics, immunology)
• T-Lymphocyte Subsets (enzymology, immunology, pathology)
• Tumor Escape (genetics)