Modulation of NKG2D-ligand Cell Surface Expression Enhances Immune Cell Therapy of Cancer

Abstract

SUMMARYA variety of immune cell therapies proposed for use in the treatment of cancer, including both autologus cells (Lymphokine Activated Killer, Cytokine Induced Killer) or cell lines (TALL-104, NK-92), rely on recognition of NKG2D ligands on malignant cells for targeting. These ligands, such as MICA and MICB in humans are stress response ligands and are commonly, but not ubiquitously expressed within tumors. Several tumor escape mechanisms have been reported, including ligand down regulation and internalization, or proteolytic cleavage and shedding of their exposed portions (releasing soluble MICA and MICB; sMICA, sMICB). Therefore, an ability to pre-screen patients for the level of tumor cell surface expression and shedding of these ligands would prevent needless treatment of patients that are unable to respond, while targeted pretreatment of patients to increase surface expression and/ or block shedding would enhance the subsequent effectiveness of these therapies. Here we report that serum tests of sMICA and sMICB in conjunction with tumor measurements might be used to determine rates of shedding from a tumor and that treatment with a selected combination of histone deacetylase inhibitors (to upregulate cell surface MICA/B in some tumors), and metalloproteinase inhibitors (to block MICA/B shedding in others) can be incorporated to regulate cell surface MICA/B levels prior to immune cell therapy, significantly enhancing their effectiveness (either used alone or as carrier vehicles for oncolytic viruses). Ultimately pre-screening patients undergoing such immune cell therapies might be used to personalize cancer treatment regimens based on the NKG2D-ligand status of the tumor.

Induction of the DNA damage response by IAP inhibition triggers natural immunity via upregulation of NKG2D ligands in Hodgkin lymphoma in vitro

“…Nevertheless, through induction of natural immunity, IAP antagonists offer a promising therapeutic approach by combating two hallmarks of cancer at the same time: apoptosis resistance and evasion from immunosurveillance (Hanahan and Weinberg, 2011). Even though we report a rather small upregulation of MICA and MICB of only about 20-25%, this is likely to be of benefit in vivo, as it was recently shown that similar levels of NKG2D ligand induction were sufficient to clearly improve tumor immunosurveillance in cervical and ovarian tumors as well as melanoma mouse models (Huang et al, 2011;Pich et al, 2013). Moreover, as antibody-based tumor therapies show very promising results (Scott et al, 2012), inclu ding substances that upregulate NKG2D ligands in future trials to evaluate the possible benefit of NKG2D-mediated cancer cell killing in addition to antibody-dependent cellular cytotoxicity, should be considered.…”

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

“…Indeed, our findings show that the combined use of MEL and marimastat enhances NK cell degranulation triggered by autologous malignant PCs. Similarly, the combination of valproate, which is known to upregulate cell surface MICA/B (25,55), and metalloproteinase inhibitors substantially stabilized cell surface MICA/B on ovarian carcinoma cells and enhanced the efficacy of immune cell therapy in vivo (56). In addition, the use of ADAM10 and ADAM17 inhibitors was shown to ameliorate the response to chemotherapy treatments in different in vivo models of cancer (57,58), and ADAM inhibitors were used in clinical trials in breast cancer patients (59).…”

Could interleukin-15 potentiate histone deacetylase inhibitor effects in haematological malignancy?

“…MICA/B mRNA and membrane protein expression were up-regulated by different HDACi, e.g., Valproic acid (VPA), sodium butyrate, FR901228, Trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), and PXD-101 in leukaemic cell lines and primary AML cells [27][28][29][30][31][32][33] and the treatment increased susceptibility to NK cells [34]. Sodium valproate and TsA reduced HDAC1 levels and enhanced histone acetylation of MICA and MICB promoters in cancer cells, augmented the expression of cell-surface NKG2D ligands, MICA/B, without increasing their soluble forms, and also increased HLA class I expression and enhanced the susceptibility to NK cell-mediated cytotoxicity [24,30,35].…”