MICA Expression Is Regulated by Cell Adhesion and Contact in a FAK/Src-Dependent Manner

Moncayo, Gerald; Lin, Dazhen; McCarthy, Michael; Watson, Aleksandra A.; O’Callaghan, Christopher A.

doi:10.3389/fimmu.2016.00687

Cited by 7 publications

(6 citation statements)

References 34 publications

(40 reference statements)

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“…As such, activated NK cells are able to recognize and lyse tumor cells expressing certain surface receptors without prior antigenic sensitization [ 8 , 9 ]. Many tumors, especially differentiated tumors, express major histocompatibility complex-class I (MHC-class I) chain related proteins A and B (MICA/B), which mark them for elimination by the NK cells [ 10 , 11 , 12 , 13 ]. However, tumor cells can successfully evade detection by NK cells by shedding MICA/B [ 11 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

ADCC against MICA/B Is Mediated against Differentiated Oral and Pancreatic and Not Stem-Like/Poorly Differentiated Tumors by the NK Cells; Loss in Cancer Patients due to Down-Modulation of CD16 Receptor

Kaur

Safaie

et al. 2021

Cancers

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Tumor cells are known to upregulate major histocompatibility complex-class I chain related proteins A and B (MICA/B) expression under stress conditions or due to radiation exposure. However, it is not clear whether there are specific stages of cellular maturation in which these ligands are upregulated or whether the natural killer (NK) cells differentially target these tumors in direct cytotoxicity or antibody-dependent cell cytotoxicity (ADCC). We used freshly isolated primary and osteoclast (OCs)-expanded NK cells to determine the degree of direct cytotoxicity or of ADCC using anti-MICA/B monoclonal antibodies (mAbs) against oral stem-like/poorly-differentiated oral squamous cancer stem cells (OSCSCs) and Mia PaCa-2 (MP2) pancreatic tumors as well as their well-differentiated counterparts: namely, oral squamous carcinoma cells (OSCCs) and pancreatic PL12 tumors. By using phenotypic and functional analysis, we demonstrated that OSCSCs and MP2 tumors were primary targets of direct cytotoxicity by freshly isolated NK cells and not by ADCC mediated by anti-MICA/B mAbs, which was likely due to the lower surface expression of MICA/B. However, the inverse was seen when their MICA/B-expressing differentiated counterparts, OSCCs and PL12 tumors, were used in direct cytotoxicity and ADCC, in which there was lower direct cytotoxicity but higher ADCC mediated by the NK cells. Differentiation of the OSCSCs and MP2 tumors by NK cell-supernatants abolished the direct killing of these tumors by the NK cells while enhancing NK cell-mediated ADCC due to the increased expression of MICA/B on the surface of these tumors. We further report that both direct killing and ADCC against MICA/B expressing tumors were significantly diminished by cancer patients’ NK cells. Surprisingly, OC-expanded NK cells, unlike primary interleukin-2 (IL-2) activated NK cells, were found to kill OSCCs and PL12 tumors, and under these conditions, we did not observe significant ADCC using anti-MICA/B mAbs, even though the tumors expressed a higher surface expression of MICA/B. In addition, differentiated tumor cells also expressed higher levels of surface epidermal growth factor receptor (EGFR) and programmed death-ligand 1(PDL1) and were more susceptible to NK cell-mediated ADCC in the presence of anti-EGFR and anti-PDL1 mAbs compared to their stem-like/poorly differentiated counterparts. Overall, these results suggested the possibility of CD16 receptors mediating both direct cytotoxicity and ADCC, resulting in the competitive use of these receptors in either direct killing or ADCC, depending on the differentiation status of tumor cells and the stage of maturation and activation of NK cells.

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Section: Introductionmentioning

confidence: 99%

ADCC against MICA/B Is Mediated against Differentiated Oral and Pancreatic and Not Stem-Like/Poorly Differentiated Tumors by the NK Cells; Loss in Cancer Patients due to Down-Modulation of CD16 Receptor

Kaur

Safaie

et al. 2021

Cancers

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“…Finally, it is important to note that, in uninfected HCT116 cells, MIC B cell surface expression levels decreased slightly from day 2 to day 4 ( Figure 3 a). This may be due to the proteolytic shedding of MIC B from the cell surface, a process that occurs during normal cell growth and the expression of MIC proteins [ 39 ].…”

Section: Resultsmentioning

confidence: 99%

Intracellular Sequestration of the NKG2D Ligand MIC B by Species F Adenovirus

Oliveira

Bouvier

2021

Viruses

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The enteric human adenoviruses of species F (HAdVs-F), which comprise HAdV-F40 and HAdV-F41, are significant pathogens that cause acute gastroenteritis in children worldwide. The early transcription unit 3 (E3) of HAdVs-F is markedly different from that of all other HAdV species. To date, the E3 proteins unique to HAdVs-F have not been characterized and the mechanism by which HAdVs-F evade immune defenses in the gastrointestinal (GI) tract is poorly understood. Here, we show that HAdV-F41 infection of human intestinal HCT116 cells upregulated the expression of MHC class I-related chain A (MIC A) and MIC B relative to uninfected cells. Our results also showed that, for MIC B, this response did not however result in a significant increase of MIC B on the cell surface. Instead, MIC B was largely sequestered intracellularly. Thus, although HAdV-F41 infection of HCT116 cells upregulated MIC B expression, the ligand remained inside infected cells. A similar observation could not be made for MIC A in these cells. Our preliminary findings represent a novel function of HAdVs-F that may enable these viruses to evade immune surveillance by natural killer (NK) cells in the infected gut, thereby paving the way for the future investigation of their unique E3 proteins.

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“…Killer receptor NKG2D-expressing immune effector cells such as Vγ9Vδ2 T cells, NK cells and some populations of TCR αβ CD8+ cytotoxic T cells which recognize the HLA class I-like molecules MICA/B, represent an essential component of the immune system's arsenal against targeted elimination of diseased tissue, i.e., transformed cells in cancer and infectious diseases (Huergo-Zapico et al, 2014). For example, the FAK/Src pathway has been shown to trigger downregulation of the MICA in cells, which is reversible with the use of focal adhesion kinase (FAK) inhibitors (Moncayo et al, 2017). Although MICA/B were recently described to be localized intracellularly in many tumor cell types (Ghadially et al, 2017), inhibition of FAK may be able to increase its expression on the cell surface to promote cell-mediated cytotoxicity.…”

Section: Using Immunological Effectors As Host-directed Therapeuticsmentioning

confidence: 99%

Microbes as Master Immunomodulators: Immunopathology, Cancer and Personalized Immunotherapies

Lérias

Paraschoudi

Sousa

et al. 2020

Front. Cell Dev. Biol.

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BACKGROUNDOur understanding of the immune system stems, in great part, from studying the host response to infection, which in most individuals leads to the absence of clinical disease and establishment of highly apt immunological memory. The host immune response in relation to opportunistic pathogens as well as to the endogenous microbiota is pivotal to deter not only infectious diseases, yet also central to providing general physiological health (Manfredo Vieira et al., 2018;

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MICA Expression Is Regulated by Cell Adhesion and Contact in a FAK/Src-Dependent Manner

Cited by 7 publications

References 34 publications

ADCC against MICA/B Is Mediated against Differentiated Oral and Pancreatic and Not Stem-Like/Poorly Differentiated Tumors by the NK Cells; Loss in Cancer Patients due to Down-Modulation of CD16 Receptor

ADCC against MICA/B Is Mediated against Differentiated Oral and Pancreatic and Not Stem-Like/Poorly Differentiated Tumors by the NK Cells; Loss in Cancer Patients due to Down-Modulation of CD16 Receptor

Intracellular Sequestration of the NKG2D Ligand MIC B by Species F Adenovirus

Microbes as Master Immunomodulators: Immunopathology, Cancer and Personalized Immunotherapies

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