title: Trastuzumab upregulates expression of HLA-ABC and T cell costimulatory molecules through engagement of natural killer cells and stimulation of IFNγ secretion.
abstract: 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+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 (IFNγ) 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 trastuzumabin vivousing 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.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate School of Biomedical Sciences, The University of Texas Health Sciences Center at Houston, Houston, TX, USA.
authors.forename: Bharat K R
authors.initials: BK
authors.lastname: Chaganty
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Songbo
authors.initials: S
authors.lastname: Qiu
authors.affiliation: Department of Pediatrics, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Srinivas S
authors.initials: SS
authors.lastname: Somanchi
authors.affiliation: Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate School of Biomedical Sciences, The University of Texas Health Sciences Center at Houston, Houston, TX, USA.
authors.forename: Dean A
authors.initials: DA
authors.lastname: Lee
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate School of Biomedical Sciences, The University of Texas Health Sciences Center at Houston, Houston, TX, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Fan
keywords: HER2; HLA-ABC; IFNγ; MHC-I; PBMC