MICA immune complex formed with alpha 3 domain-specific antibody activates human NK cells in a Fc-dependent manner

Du, Changchun; Bevers, Jack; Cook, Ryan; Lombana, T. Noelle; Rajasekaran, Kamalakannan; Matsumoto, Marissa L.; Spiess, Christoph; Kim, Jeong M.; Ye, Zhengmao

doi:10.1186/s40425-019-0687-9

Cited by 17 publications

(15 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…34,36 In line with this suggestion, the levels of HCP5 were signifi- receptors on their own surface. 30,31,[37][38][39] It is possible that one mechanism by which rs2844511 could modify cervical cancer risk is the regulation of MICA expression and subsequent immune-surveillance of tumor cells. From the results of our study, the risk allele of rs2844511 associated with increased MICA levels in HPV negative (normal) cervical epithelium, but this was reversed in HPV infected cells.…”

Section: Discussionmentioning

confidence: 99%

“…Little surface expression of MICA is seen in healthy cells; however, most epithelial tumor cells express MICA. There are multiple modes through which cervical cancer cells evolve to evade this detection, including the secretion of MICA in a soluble form to block NKG2D receptors or the aberrant expression of NKG2D receptors on their own surface 30,31,37‐39 . It is possible that one mechanism by which rs2844511 could modify cervical cancer risk is the regulation of MICA expression and subsequent immune‐surveillance of tumor cells.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Association of genomic variants at the human leukocyte antigen locus with cervical cancer risk, HPV status and gene expression levels

Ramachandran

Schürmann

Mao

et al. 2020

Intl Journal of Cancer

View full text Add to dashboard Cite

The human leukocyte antigen (HLA) locus on chromosome 6 has been reported to be associated with cervical cancer. We investigated two independent single‐nucleotide polymorphisms in a large case‐control series of cervical dysplasia and carcinoma that has been newly established by the German Cervigen Consortium, comprising a total of 2481 cases and 1556 healthy females. We find significant associations for both variants, rs9272117 at HLA‐DQA1 and rs2844511 at MICA and HCP5, with cervical disease. Both variants showed evidence of association with invasive cervical cancer (rs9272117: OR 0.89, 95% CI 0.79‐0.99, P = .036; rs2844511: OR 1.17, 95% CI 1.04‐1.31, P = .008) and with high‐grade dysplasia (rs9272117: OR 0.78, 95% CI 0.70‐0.87, P = 7.1 × 10−6; rs2844511: OR 1.13, 95% CI 1.01‐1.26, P = .035), as well as in a combined analysis of both groups (rs9272117: OR 0.83, 95% CI 0.75‐0.91, P = 6.9 × 10−5; rs2844511: OR 1.14, 95% CI 1.04‐1.26, P = .005). Variant rs2844511, but not rs9272117, also showed modest evidence of association with low‐grade dysplasia (OR 1.26, 95% CI 1.04‐1.54, P = .019). In case‐only analyses, rs2844511 tended to predict HPV status (P = .044) and rs9272117 tended to associate with HPV16 (P = .022). RNA studies in cervical samples showed a significant correlation in the transcript levels of MICA, HCP5 and HLA‐DQA1, suggesting extensive co‐regulation. All three genes were upregulated in HPV16‐positive samples. In stratified analyses, rs9272117 was associated with HLA‐DQA1 levels, specifically in HPV‐positive samples, while rs2844511 was associated with MICA and HCP5 levels. The risk allele of rs2844511 was required for correlations between MICA or HCP5 with HLA‐DQA1. Altogether, our results support 6p21.32‐33 as the first consistent cervical cancer susceptibility locus and provide evidence for a link between genetic risk variants, HPV16 status and transcript levels of HLA‐DQA1, HCP5 and MICA, which may contribute to tumor immune evasion.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Association of genomic variants at the human leukocyte antigen locus with cervical cancer risk, HPV status and gene expression levels

Ramachandran

Schürmann

Mao

et al. 2020

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…Another likelihood is that a single MICA or MICB ligand may not be sufficient to trigger early state of NK or CIK cells as described in an early study [ 41 ]. Interestingly, a recent study showed that the α3 domain-specific MICA antibody could completely reverse the soluble MICA-mediated NK cell suppression in a Fc-dependent manner [ 42 ]. Regardless, targeting the NKG2D-NKG2D ligand axis has been becoming a promising avenue on the way to fight against malignant diseases.…”

Section: Discussionmentioning

confidence: 99%

Increase of Antitumoral Effects of Cytokine-Induced Killer Cells by Antibody-Mediated Inhibition of MICA Shedding

Zhang

et al. 2020

Cancers

View full text Add to dashboard Cite

Natural killer group 2D (NKG2D) receptor plays a pivotal role in cytokine-induced killer (CIK) cell-mediated cytotoxicity against malignancies, and the expression of NKG2D ligands might allow targets to be more susceptible to the CIK cell-mediated destruction. In this study, we investigated the synergistic effects of CIK cells antitumor activity and antibody-mediated inhibition of MICA/B shedding. This monoclonal antibody (7C6) has been previously shown to be able to specifically target MICA/B a3 domain on tumor cells, resulting in the increase in cell surface MICA/B expression by inhibition of their shedding. In the current study, we show that 7C6 antibody could substantially inhibit MICA shedding and stabilize the expression of MICA/B on Hela cells and MDA-MB-231 cells. In combination with 7C6, CIK cells showed higher degranulation rate, more IFN-γ production and elevated cytotoxic capacity against tumor cells. Furthermore, we demonstrate that NKG2D-MICA/B ligation could lead to activation of both CD3+ CD56− T cells and CD3+CD56+ NKT subset cells of CIK culture and NKT subset was more sensitive to NKG2D signaling than the counterpart T cells. 7C6-mediated inhibition of MICA shedding could strengthen this signal and eventually enhance the antitumor activity of CIK cells. With multiple advantages of easy ex vivo expansion, minor GVHD, natural tumor trafficking and non-MHC restricted, CIK cell-based therapy may serve as a potent combination partner with MICA antibody-mediated immunotherapy.

show abstract

“…3 ). 209 – 216 In particular, targeting the NKG2D/soluble MIC, which is highly expressed in many malignant carcinoma cells (like melanoma and leukemia), maybe a potential approach for the treatment of these cancers.…”

Section: Activating Immune Checkpoint Receptorsmentioning

confidence: 99%

Immune checkpoint molecules in natural killer cells as potential targets for cancer immunotherapy

Cao

Wang

Jin

et al. 2020

Sig Transduct Target Ther

View full text Add to dashboard Cite

Recent studies have demonstrated the potential of natural killer (NK) cells in immunotherapy to treat multiple types of cancer. NK cells are innate lymphoid cells that play essential roles in tumor surveillance and control that efficiently kill the tumor and do not require the major histocompatibility complex. The discovery of the NK’s potential as a promising therapeutic target for cancer is a relief to oncologists as they face the challenge of increased chemo-resistant cancers. NK cells show great potential against solid and hematologic tumors and have progressively shown promise as a therapeutic target for cancer immunotherapy. The effector role of these cells is reliant on the balance of inhibitory and activating signals. Understanding the role of various immune checkpoint molecules in the exhaustion and impairment of NK cells when their inhibitory receptors are excessively expressed is particularly important in cancer immunotherapy studies and clinical implementation. Emerging immune checkpoint receptors and molecules have been found to mediate NK cell dysfunction in the tumor microenvironment; this has brought up the need to explore further additional NK cell-related immune checkpoints that may be exploited to enhance the immune response to refractory cancers. Accordingly, this review will focus on the recent findings concerning the roles of immune checkpoint molecules and receptors in the regulation of NK cell function, as well as their potential application in tumor immunotherapy.

show abstract

MICA immune complex formed with alpha 3 domain-specific antibody activates human NK cells in a Fc-dependent manner

Cited by 17 publications

References 35 publications

Association of genomic variants at the human leukocyte antigen locus with cervical cancer risk, HPV status and gene expression levels

Association of genomic variants at the human leukocyte antigen locus with cervical cancer risk, HPV status and gene expression levels

Increase of Antitumoral Effects of Cytokine-Induced Killer Cells by Antibody-Mediated Inhibition of MICA Shedding

Immune checkpoint molecules in natural killer cells as potential targets for cancer immunotherapy

Contact Info

Product

Resources

About