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.
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.
Immune and Gene Therapy Laboratory, Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institute, 171 76 Stockholm, Sweden.
Riki
R
Okita
Dimitrios
D
Mougiakakos
Takashi
T
Ando
Yumeng
Y
Mao
Dhifaf
D
Sarhan
Erik
E
Wennerberg
Barbara
B
Seliger
Andreas
A
Lundqvist
Kousaku
K
Mimura
Rolf
R
Kiessling
D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000502:physiology*; D020893:Receptor, ErbB-3 / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D019139:Tumor Escape / Q000235:genetics
D015395:Histocompatibility Antigens Class I; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C099187:MHC class I-related chain A; C098080:MICB antigen; C508053:ERBB2 protein, human