title: NK cell-mediated antibody-dependent cellular cytotoxicity is enhanced by tamoxifen in HER2/neu non-amplified, but not HER2/neu-amplified, breast cancer cells.
abstract: Tumor-targeting antibodies have been successful in the treatment of various types of cancers. Antibodies engage the immune system with their Fc, stimulating immune cell effector function. In the clinic, FcγRIIIa polymorphisms with higher affinity for the Fc of antibodies were shown to improve response rates and overall survival. Efforts have been made to modify the Fc to enhance affinity to Fc receptors and thereby improve effector function. An alternative for improving immune effector function may be to increase the level of tumor antigen expression. In this study, tamoxifen was used to increase HER2/neu protein level to determine whether increased tumor antigen expression could enhance NK cell-mediated antibody-dependent cytotoxicity (ADCC). Tamoxifen was found to increase HER2/neu 1.5-fold to threefold in breast cancer cell lines that were HER2/neu non-amplified. Using flow cytometry to simultaneously evaluate NK cell degranulation and tumor cell death, the increase in HER2/neu enhanced NK cell-mediated ADCC. However, in cells that had HER2/neu gene amplification and estrogen receptor expression, tamoxifen elevated HER2/neu but failed to improve NK cell function. The quantity of HER2/neu on the tumor cell surface was approximately double that of the number of Fc receptors found on NK cells. This appears to reflect a ceiling at which increasing antigen expression fails to improve NK cell effector function. This has clinical implications as trying to increase antigen expression to enhance NK cell function may be useful for patients with antigen-low tumors, but not in those whose tumors have gene amplification or high levels of antigen expression.
authors: Immunotherapy Research Laboratory, Aurora St. Luke's Medical Center, Aurora Health Care, Milwaukee, WI, USA. john.richards@aurora.org.|Aurora Research Institute, Aurora Health Care, Milwaukee, WI, USA. john.richards@aurora.org.|Immunology Research Laboratory, Aurora Research Institute, 960 N. 12th Street, 3rd Floor, Milwaukee, WI, 53233, USA. john.richards@aurora.org.
authors: John O
authors: JO
authors: Richards
authors: Immunotherapy Research Laboratory, Aurora St. Luke's Medical Center, Aurora Health Care, Milwaukee, WI, USA.|Aurora Research Institute, Aurora Health Care, Milwaukee, WI, USA.
authors: Alex J
authors: AJ
authors: Albers
authors: Immunotherapy Research Laboratory, Aurora St. Luke's Medical Center, Aurora Health Care, Milwaukee, WI, USA.|Aurora Research Institute, Aurora Health Care, Milwaukee, WI, USA.
authors: Thomas S
authors: TS
authors: Smith
authors: Aurora Research Institute, Aurora Health Care, Milwaukee, WI, USA.|Surgical Breast Oncology, Aurora Cancer Care, Aurora Health Care, Milwaukee, WI, USA.
authors: Judy A
authors: JA
authors: Tjoe
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D015550:Cell Degranulation / Q000187:drug effects; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D061986:MCF-7 Cells; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011961:Receptors, Fc / Q000378:metabolism; D013629:Tamoxifen / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D011961:Receptors, Fc; D013629:Tamoxifen; C508053:ERBB2 protein, human
keywords: ADCC; Antibodies; Antigen expression; Flow cytometry; HER2/neu; NK cells