Overexpression of protectin (CD59) down-modulates the susceptibility of human melanoma cells to homologous complement

Coral, Sandra; Fonsatti, Ester; Sigalotti, Luca; Nardo, Chiara De; Visintin, Alberto; Nardi, Gianpaolo; Colizzi, Francesca; Colombo, Mario P.; Romano, Gaetano; Altomonte, Maresa; Maio, Michele

doi:10.1002/1097-4652(200012)185:3<317::aid-jcp1>3.0.co;2-l

Cited by 24 publications

(3 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Concerning CD59, it should be noted that this membrane-bound complement regulatory protein is one of the antigens typically expressed on the surface of cancer cells, whatever their origination. Its increasing concentration was found to be associated with resistance to cell lysis, hence enhancing and promoting tumor growth and expansion [31,32]. However, the expression of CD antigens is equivocally interpreted: for example, the expression of CD55 is associated with colorectal carcinoma [33], but the loss of CD55 is associated with breast cancer [34,35].…”

Section: Implication Of Complement Systems In Crc Development and Surmentioning

confidence: 99%

Revelation of Proteomic Indicators for Colorectal Cancer in Initial Stages of Development

et al. 2020

View full text Add to dashboard Cite

Background: Colorectal cancer (CRC) at a current clinical level is still hardly diagnosed, especially with regard to nascent tumors, which are typically asymptotic. Searching for reliable biomarkers of early diagnosis is an extremely essential task. Identification of specific post-translational modifications (PTM) may also significantly improve net benefits and tailor the process of CRC recognition. We examined depleted plasma samples obtained from 41 healthy volunteers and 28 patients with CRC at different stages to conduct comparative proteome-scaled analysis. The main goal of the study was to establish a constellation of protein markers in combination with their PTMs and semi-quantitative ratios that may support and realize the distinction of CRC until the disease has a poor clinical manifestation. Results: Proteomic analysis revealed 119 and 166 proteins for patients in stages I–II and III–IV, correspondingly. Plenty of proteins (44 proteins) reflected conditions of the immune response, lipid metabolism, and response to stress, but only a small portion of them were significant (p < 0.01) for distinguishing stages I–II of CRC. Among them, some cytokines (Clusterin (CLU), C4b-binding protein (C4BP), and CD59 glycoprotein (CD59), etc.) were the most prominent and the lectin pathway was specifically enhanced in patients with CRC. Significant alterations in Inter-alpha-trypsin inhibitor heavy chains (ITIH1, ITIH2, ITIH3, and ITIH4) levels were also observed due to their implication in tumor growth and the malignancy process. Other markers (Alpha-1-acid glycoprotein 2 (ORM2), Alpha-1B-glycoprotein (A1BG), Haptoglobin (HP), and Leucine-rich alpha-2-glycoprotein (LRG1), etc.) were found to create an ambiguous core involved in cancer development but also to exactly promote tumor progression in the early stages. Additionally, we identified post-translational modifications, which according to the literature are associated with the development of colorectal cancer, including kininogen 1 protein (T327-p), alpha-2-HS-glycoprotein (S138-p) and newly identified PTMs, i.e., vitamin D-binding protein (K75-ac and K370-ac) and plasma protease C1 inhibitor (Y294-p), which may also contribute and negatively impact on CRC progression. Conclusions: The contribution of cytokines and proteins of the extracellular matrix is the most significant factor in CRC development in the early stages. This can be concluded since tumor growth is tightly associated with chronic aseptic inflammation and concatenated malignancy related to loss of extracellular matrix stability. Due attention should be paid to Apolipoprotein E (APOE), Apolipoprotein C1 (APOC1), and Apolipoprotein B-100 (APOB) because of their impact on the malfunction of DNA repair and their capability to regulate mTOR and PI3K pathways. The contribution of the observed PTMs is still equivocal, but a significant decrease in the likelihood between modified and native proteins was not detected confidently.

show abstract

Section: Implication Of Complement Systems In Crc Development and Surmentioning

confidence: 99%

Revelation of Proteomic Indicators for Colorectal Cancer in Initial Stages of Development

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The complement is an important player in Ab-induced tumor cell death, and therefore, it has a major impact on the efficacy of therapeutic IgG1 monoclonal Abs, such as trastuzumab 29 . However, highly expressed mCRPs may block the complement pathway and thus protect tumor cells from mAb-induced CDC 30 . Consistent with the results, we showed that a NANOG high tumor with CTL-refractory property exhibited resistance to trastuzumab-mediated CDC, whereas silencing of NANOG led to increase in susceptibility of trastuzumab-mediated CDC.…”

Section: Discussionmentioning

confidence: 99%

NANOG confers resistance to complement-dependent cytotoxicity in immune-edited tumor cells through up-regulating CD59

Son

Cho

et al. 2022

Sci Rep

View full text Add to dashboard Cite

Cancer immunoediting drives the adaptation of tumor cells to host immune surveillance. Previously, we have demonstrated that immunoediting driven by cytotoxic T lymphocytes (CTLs) enriches NANOG+ tumor cells with immune-refractory properties. Here, we found that CTL-mediated immune pressure triggered cross-resistance of tumor cells to the complement system, a part of the innate immune system. In this process, NANOG upregulated the membrane-bound complement regulatory protein (mCRP) CD59 through promoter occupancy, thereby contributing to the resistance of tumor cells against complement-dependent cytotoxicity (CDC). Notably, targeting of NANOG sensitized the immune-refractory tumor cells to trastuzumab-mediated CDC. Collectively, our results revealed a possible mechanism through which selection imposed by T-cell based immunotherapy triggered complement-resistant phenotypes in the tumor microenvironment (TME), by establishing a firm molecular link between NANOG and CD59 in immune-edited tumor cells. We believe these results hold important implications for the clinical application of CDC-mediated therapeutic antibody.

show abstract

“…When investigating whether positive cytotoxic effects found with MeWo were also present in other melanoma cell lines, we observed that five other melanoma cells tested were practically resistant to the plasma‐derived cytotoxic attack. It is known that melanoma cells express CD46, CD55 and to a larger extent CD59, which inhibit complement‐mediated cytotoxicity . Therefore, we tested CD46, CD55 and CD59 expression on our cell lines.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic activity against human neuroblastoma and melanoma cells mediated by IgM antibodies derived from peripheral blood of healthy donors

Devarapu

Mamidi

Plöger

et al. 2016

Intl Journal of Cancer

View full text Add to dashboard Cite

A small percentage of healthy donors identified in the Western population carry antibodies in their peripheral blood which convey cytotoxic activity against certain human melanoma and neuroblastoma cell lines. We measured the cytotoxic activity of sera and plasmas from healthy donors on the human neuroblastoma cell line Kelly and various melanoma cell lines. Antibodies of IgM isotype, presumably belonging to the class of naturally occurring antibodies, exerted cytotoxic activity in a complement-dependent fashion. Apart from complement-dependent tumor cell lysis, we observed C3 opsonization in all tumor cell lines upon treatment with cytotoxic plasmas. Cell lines tested primarily expressed membrane complement regulatory proteins (mCRP) CD46, CD55 and CD59 to various extents. Blocking of mCRPs by monoclonal antibodies enhanced cell lysis and opsonization, though some melanoma cells remained resistant to complement attack. Epitopes recognized by cytotoxic antibodies were represented by gangliosides such as GD2 and GD3, as evidenced by cellular sialidase pretreatment and enhanced expression of distinct gangliosides. It remains to be clarified why only a small fraction of healthy persons carry these antitumor cytotoxic antibodies. oligosaccharide-specific monoclonal antibodies or by vaccination with tumor-associated oligosaccharides. For example, treatment with antiganglioside antibodies caused regression of neuroblastoma, 3,4 and clinical trials have been performed using the anti-GD3 monoclonal antibody (mAb) R24 for passive immunization in melanoma patients. 5 In melanoma patients, the level of antiganglioside antibodies was significantly increased after vaccination with a cocktail of gangliosides, and antibody titers correlated with patients' survival. 6 Within the Western population a small proportion of healthy persons carry, within their pool of circulating immunoglobulins, antibodies, preferentially of IgM isotype which can cause a complement-mediated cytolysis of human neuroblastoma cells. 7,8 There are strong indications that these antibodies belong to the class of naturally occurring antibodies (nAb) that are present without external stimulation as products of germ-line encoded genes of the variable region 9,10 and further that a majority of IgM nAb react with carbohydrate antigens. IgM nAb are involved in homeostasis by clearance of damaged or modified intracellular plasma proteins, oxidized lipoproteins or dying cells. 11 Functions attributed to IgM are neutralization, opsonization and complement activation. IgM nAb bind to invading pathogens, which results in complement activation and lysis of the invaders as first line of defense. 11

show abstract

Overexpression of protectin (CD59) down-modulates the susceptibility of human melanoma cells to homologous complement

Cited by 24 publications

References 22 publications

Revelation of Proteomic Indicators for Colorectal Cancer in Initial Stages of Development

Revelation of Proteomic Indicators for Colorectal Cancer in Initial Stages of Development

NANOG confers resistance to complement-dependent cytotoxicity in immune-edited tumor cells through up-regulating CD59

Cytotoxic activity against human neuroblastoma and melanoma cells mediated by IgM antibodies derived from peripheral blood of healthy donors

Contact Info

Product

Resources

About