MICA-Expressing Monocytes Enhance Natural Killer Cell Fc Receptor-Mediated Antitumor Functions

Campbell, Amanda R.; Duggan, Megan; Suarez‐Kelly, Lorena P.; Bhave, Neela; Opheim, Kallan S.; McMichael, Elizabeth L.; Trikha, Prashant; Parihar, Robin; Luedke, Eric; Lewis, Adrian; Yung, Bryant C.; Lee, Robert; Raulet, David H.; Tridandapani, Susheela; Groh, Veronika; Yu, Lianbo; Yıldız, Vedat; Byrd, John C.; Caligiuri, Michael A.; Carson, William E.

doi:10.1158/2326-6066.cir-16-0005

Cited by 12 publications

(12 citation statements)

References 47 publications

(49 reference statements)

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“…Importantly, some of the few immune genes that are downregulated following BAP1 loss (MICA, TNFSF13, and CD44) are important for the activation of anti-tumour immune responses [25][26][27], as shown in box and whisker plots together with other immunosuppressive and exhaustion-related genes (i.e. HLA-DOB, CD74, CD38, LGALS3, IDO1, TIGIT, LAG3, and CD96) ( Figure 2D).…”

Section: Bap1 Loss Correlates With Immunosuppressive Network In Pummentioning

confidence: 99%

Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development

Figueiredo

Kalirai

Sacco

et al. 2020

The Journal of Pathology

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Immunotherapy using immune checkpoint inhibitors (ICIs) induces durable responses in many metastatic cancers. Metastatic uveal melanoma (mUM), typically occurring in the liver, is one of the most refractory tumours to ICIs and has dismal outcomes. Monosomy 3 (M3), polysomy 8q, and BAP1 loss in primary uveal melanoma (pUM) are associated with poor prognoses. The presence of tumour‐infiltrating lymphocytes (TILs) within pUM and surrounding mUM – and some evidence of clinical responses to adoptive TIL transfer – strongly suggests that UMs are indeed immunogenic despite their low mutational burden. The mechanisms that suppress TILs in pUM and mUM are unknown. We show that BAP1 loss is correlated with upregulation of several genes associated with suppressive immune responses, some of which build an immune suppressive axis, including HLA‐DR, CD38, and CD74. Further, single‐cell analysis of pUM by mass cytometry confirmed the expression of these and other markers revealing important functions of infiltrating immune cells in UM, most being regulatory CD8+ T lymphocytes and tumour‐associated macrophages (TAMs). Transcriptomic analysis of hepatic mUM revealed similar immune profiles to pUM with BAP1 loss, including the expression of IDO1. At the protein level, we observed TAMs and TILs entrapped within peritumoural fibrotic areas surrounding mUM, with increased expression of IDO1, PD‐L1, and β‐catenin (CTNNB1), suggesting tumour‐driven immune exclusion and hence the immunotherapy resistance. These findings aid the understanding of how the immune response is organised in BAP1 − mUM, which will further enable functional validation of detected biomarkers and the development of focused immunotherapeutic approaches. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Bap1 Loss Correlates With Immunosuppressive Network In Pummentioning

confidence: 99%

Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development

Figueiredo

Kalirai

Sacco

et al. 2020

The Journal of Pathology

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“…This idea is supported by another study showing that expression of RAE-1 by murine macrophages downregulates NKG2D surface expression by NK cells and inhibits the NK cell response against B16 tumors ( 41 ). MICA expression by human monocytes was also shown to enhance NK cell interferon gamma (IFN-γ) production and antitumor function via an NKG2D-dependent mechanism ( 42 , 43 ).…”

Section: Function Of Nkg2d Ligand Expression By Monocytes and Macrophmentioning

confidence: 99%

More than Decoration: Roles for Natural Killer Group 2 Member D Ligand Expression by Immune Cells

Trembath

Markiewicz

2018

Front. Immunol.

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The activating immune receptor natural killer group 2 member D (NKG2D), which is expressed by natural killer cells and T cell subsets, recognizes a number of ligands expressed by “stressed” or damaged cells. NKG2D has been extensively studied for its role in tumor immunosurveillance and antiviral immunity. To date, the majority of studies have focused on NKG2D-mediated killing of target cells expressing NKG2D ligands. However, with a number of reports describing expression of NKG2D ligands by cells that are not generally considered stressed, it is becoming clear that some healthy cells also express NKG2D ligands. Expression of these ligands by cells within the skin, intestinal epithelium, and the immune system suggests other immune functions for NKG2D ligand expression in addition to its canonical role as a “kill me” signal. How NKG2D ligands function in this capacity is just now starting to be unraveled. In this review, we examine the expression of NKG2D ligands by immune cells and discuss current literature describing the effects of this expression on immunity and immune regulation.

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“…We recently demonstrated the involvement of NKG2D in the induction of trastuzumab-mediated ADCC by NK cells [ 21 ], which could explain the synergism between trastuzumab and taxanes in clinical trials [ 22 ]—NKG2D expression on NK cells is increased by taxanes and is associated with NK cytotoxic activity [ 21 ]. Moreover, NKG2D receptor on NK cells binds to MICA, one of its ligands, on monocytes that reside in the tumor microenvironment, boosting NK cell antitumor activity against Ab-coated tumor cells and ultimately increasing their production of interferon- γ (IFN γ ) [ 23 ].…”

Section: Mechanisms Of Action Of Her2-targeting Agentsmentioning

confidence: 99%

Predicting the Efficacy of HER2-Targeted Therapies: A Look at the Host

2017

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HER2 is overexpressed in 20% of invasive breast cancers (BCs) and correlates with a more aggressive disease. Until the advent of targeted agents, HER2 was associated with worse outcomes. Rationally designed HER2-targeted agents have been developed and introduced into clinical practice for women with HER2-amplified BC, improving disease-free and overall survival for primary and metastatic tumors. Trastuzumab, a recombinant humanized anti-HER2 monoclonal antibody, combined with chemotherapy, remains the standard of care for patients with HER2-positive BCs. However, many patients do not respond to this agent, whereas newer drugs have proven to be efficacious in clinical trials. The identification of biomarkers that select sensitive tumors and patients who will benefit from these new agents would help the incorporation of these therapies, limiting the risk of side effects and overtreatment and improving the outcomes of all patients with early-stage HER2-positive BC. We review the mechanisms of action of HER2-targeting agents, focusing on the involvement of the immune system and related predictive biomarkers.

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MICA-Expressing Monocytes Enhance Natural Killer Cell Fc Receptor-Mediated Antitumor Functions

Cited by 12 publications

References 47 publications

Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development

Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development

More than Decoration: Roles for Natural Killer Group 2 Member D Ligand Expression by Immune Cells

Predicting the Efficacy of HER2-Targeted Therapies: A Look at the Host

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