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 C 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 (IFNg) 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 trastuzumab in vivo using 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.

Blockade of CD112R and TIGIT signaling sensitizes human natural killer cell functions

“…It is also unclear how effective the combinatory therapy of TIGIT/CD112R blockade and trastuzumab will be in human breast cancer therapy in vivo . Adaptive immunity, mainly mediated by T cells, is known to be essential for trastuzumab therapy of breast cancer [23,24]. Besides NK cells, TIGIT and CD112R are also known to be key checkpoints for T cells [17,25].…”

Immunotherapy: A Challenge of Breast Cancer Treatment

“…Similarly, in normal and cancerous breast tissues, HLA-I expression is inversely correlated with the expression of estrogen receptors, which may be related to the low level of tumor-infiltrating lymphocytes [93], and hence, with the failure of the T-cell cytotoxic response. It is worth emphasizing at this point that provided that agents targeting different protein kinases such as Mitogen Activated Protein Kinase (MAPK) or HER2 may increase HLA-I expression in breast cancer cells [97,98], the use of kinase inhibitors would be a valuable strategy to increase the antitumor effects of T-cell based immunotherapies. Similarly, strategies aimed at inducing HLA-II expression in tumor cells may be valuable tools to increase patient response and prognosis to such therapies [96].…”

Modeling Basins of Attraction for Breast Cancer Using Hopfield Networks

“…The biomarker ascending curve matches the density descending curve, and the biomarker descending curve matches the density ascending curve. also activates the HLA-A antigen, involved in the immune response (Chaganty et al, 2015). The MEL-18 gene (or PCGF2) was classified in the transcription biological process.…”