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

• Published in: International journal of cancer Vol. 138; no. 12; pp. 2963 - 2973
• Main Authors: Devarapu, Satish Kumar, Mamidi, Srinivas, Plöger, Frank, Dill, Othmar, Blixt, Ola, Kirschfink, Michael, Schwartz‐Albiez, Reinhard
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 15.06.2016
• Subjects: Antibody-Dependent Cell Cytotoxicity; antitumor cytotoxic natural antibodies; Biomarkers, Tumor - immunology; Cancer; Cell Line, Tumor; Cytotoxicity; Epitopes - immunology; gangliosides; Gangliosides - immunology; Healthy Volunteers; human plasma; Humans; Immunoglobulin M - blood; Immunoglobulin M - immunology; Immunoglobulins; Medical research; Melanoma; Melanoma - immunology; membrane complement receptor proteins; Neuroblastoma; Neuroblastoma - immunology; gangliosides; neuroblastoma; melanoma; antitumor cytotoxic natural antibodies; human plasma; membrane complement receptor proteins
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.30025

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. What's new? A small percentage of healthy blood donors carry IgM antibodies that react with carbohydrate antigens, including tumor‐associated gangliosides GD2 and GD3. Ganglioside‐targeting IgM can kill via complement activation, however, remains unclear. In this study, donor IgM antibodies effectively killed human neuroblastoma Kelly cells and certain melanoma cells in vitro, using distinct gangliosides as targets for cytotoxic attack. Complement attack was countered, however, by membrane complement regulator proteins (mCRPs), which are highly expressed on most melanoma cells. Despite neutralization with anti‐mCRP antibodies, some melanoma cells maintained resistance, suggesting that humoral anti‐melanoma activity is prevented through other mechanisms.