Antibodies reactive with the protein core of MUC1 mucin are present in ovarian cancer patients and healthy women

Richards, E.; Pl, Devine; Quin, Rachel J.; Fontenot, J. D.; Ward, BG; McGuckin, Michael A.

doi:10.1007/s002620050484

Cited by 66 publications

(55 citation statements)

References 21 publications

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“…[33][34][35][36] In this regard, it is of note that specifically blocking the function of a complement regulatory protein without coadmin- In conclusion, the data presented fully support the hypothesis that reversing the effects of complement regulatory proteins expressed on a tumor cell surface will allow more effective immunemediated clearance of tumor cells and improve prospects for successful immunotherapy. The results justify further research and development of strategies to inhibit or downregulate complement regulatory proteins on tumor cells.…”

Section: Discussionsupporting

confidence: 55%

Inhibition of a complement regulator in vivo enhances antibody therapy in a model of mammary adenocarcinoma

Imai

Ohta

Okada

et al. 2004

Intl Journal of Cancer

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Key words: complement, Crry, inhibitor, antibody therapyComplement effector systems involved in an immune response to tumor cells can include the amplification of an inflammatory response, recruitment of immune effector cells, opsonization of tumor cells that result in complement-dependent cell-mediated cytotoxicity (CDCC) and enhanced antibody-dependent cell-mediated cytoxicity (ADCC), and direct complement mediated lysis. Normal and tumor cells are protected from complement by the expression of membrane bound complement regulatory proteins, and these proteins are upregulated on some cancers. 1-5 Regulators of complement activation are decay accelerating factor (DAF), membrane cofactor proteins (MCP) and, in rodents only, Crry. Rodent Crry is a structural and functional analog of DAF and MCP. These proteins act early in the pathway and limit C3 deposition/opsonization. CD59 regulates the terminal pathway of complement and controls formation of the cytolytic membrane attack complex (MAC).Many in vitro studies have shown that blocking the function of membrane-bound complement regulatory proteins sensitizes normally resistant tumor cells to antibody-mediated complement deposition and lysis (reviewed in references 6 -8). Complement regulatory proteins expressed on tumor cells have also been shown to enhance tumorigenesis in rodent models. 9 -11 These results have lead to the hypothesis that inhibiting the function of complement regulatory proteins expressed on tumor cells will enhance antibody immunotherapy. However, complement regulatory proteins are widely expressed on normal cells, and targeting inhibitory molecules to complement regulators expressed on tumor cells in vivo is a technical challenge. As a consequence, the effect of inhibiting complement regulatory proteins on tumor cells has not been investigated in a therapeutic protocol in vivo.In the short term, untargeted inhibitors of complement regulatory proteins may not pose serious health concerns in the absence of a specific complement activation signal (e.g., a specific antibody), but a "sink" effect would certainly be a barrier to effectiveness. One approach for targeting and inhibiting complement regulators on tumor cells that has been evaluated in vitro is the use of bispecific antibodies. Bispecific antibodies that recognize both a tumor-associated antigen and a complement regulatory protein (function blocking) have been shown to selectively target and enhance complement sensitivity of tumor cells in vitro. [12][13][14] Nevertheless, the development of bispecific antibodies with relevant specificities for in vivo and clinical testing needs to be preceded by animal testing to show that the concept can be translated into effective cancer therapy. We have investigated whether inhibiting a complement regulatory protein on tumor cells in vivo represents a viable strategy with regard to effect on antibody and complement dependent immune response and therapeutic outcome. For our feasibility study, we use a cancer model consisting of the Crrypositive 13762...

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Section: Discussionsupporting

confidence: 55%

Inhibition of a complement regulator in vivo enhances antibody therapy in a model of mammary adenocarcinoma

Imai

Ohta

Okada

et al. 2004

Intl Journal of Cancer

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“…We and others demonstrated that MUC1-specific antibodies are associated with a better prognosis in breast, pancreatic, lung, and ovarian cancer (23)(24)(25)(26). Similarly, the presence of T cells in tumors has been associated with better prognosis in lung, ovarian, and colon cancer (27)(28)(29).…”

Section: Discussionmentioning

confidence: 96%

Healthy individuals have T-cell and antibody responses to the tumor antigen cyclin B1 that when elicited in mice protect from cancer

Vella

Fuhrmann³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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We previously identified the aberrantly expressed cell cycle regulator cyclin B1 as a tumor antigen recognized by antibodies and T cells from patients with breast, lung, and head and neck cancers. Ordinarily expressed only transiently in the G2/M stage of the cell cycle in normal cells, cyclin B1 is constitutively expressed at high levels in the cytoplasm of these and many other tumor types, leading to its recognition by the cancer patient's immune system. We report here an unexpected observation that cyclin B1-specific antibody and memory CD4 and CD8 T cells are also found in many healthy individuals who have no history of cancer. Moreover, young as well as older healthy people have these responses suggesting that events other than cancer, which occur either early in life or throughout life, may lead to aberrant cyclin B1 expression and anti-cyclin B1 immunity. The role, if any, of immunity to this tumor-associated antigen is not known. We wanted to determine specifically whether immunity to cyclin B1 might be important in the immunosurveillance of cyclin B1؉ tumors. We therefore tested in mice the effectiveness of vaccine-elicited anticyclin B1 immunity against a cyclin B1؉ mouse tumor that was chosen based on our published observation that cyclin B1 overexpression is associated with the lack of p53 function. We found that cyclin B1 DNA prime-protein boost vaccine protected mice from a challenge with a tumor cell line that was established from a tumor arising in the p53 ؊/؊ mouse that spontaneously overexpresses cyclin B1.cancer vaccines ͉ human immunology ͉ immunosurveillance ͉ tumor immunology O verexpression of cyclin B1 has been documented in many human cancers, including colorectal, lung, cervical, and head and neck carcinomas (1-5). Additionally, this overexpression has been shown to correlate with worse prognosis in lung, laryngeal, esophageal, and tongue cancers (1,3,(5)(6)(7)(8). Whereas cyclin B1 is expressed transiently in normal cells, in cancer cells, it is expressed constitutively in all stages of the cell cycle (9). Additionally, cancer-associated cyclin B1 overexpression is evident primarily in the cytoplasm where it can be subject to proteasomal processing and presentation in MHC class I. We reported isolation of cyclin B1 peptides from MHC class I molecules of tumor cells that were recognized by tumor-specific memory T cells present in patients with cyclin B1 overexpressing tumors (10). We later showed that patients with cancer and premalignant lesions that overexpress cyclin B1 have cyclin B1-specific antibodies of IgM, IgG and IgA isotypes (11).Cyclin B1 overexpression in many tumors is secondary to the loss of p53 function either through p53 mutations or a deletion (9). Considering that alterations in p53 function happen in many tumors early in the process of transformation, cyclin B1 is a good candidate antigen for both immunotherapy and immunoprevention of a large number of human tumors. Additionally, because cyclin B1 is required for entry into mitosis, it is unlikely that a growing tum...

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“…Anti-MUC1 antibodies have been described and correlated with a more favorable prognosis (2)(3)(4)(5) showing that patients generate immunity against MUC1 produced by their tumors and defining MUC1 as a tumor-associated antigen and candidate for cancer vaccines (6). Anti-MUC1 antibodies are also found in healthy individuals, especially in women during pregnancy and lactation.…”

Section: Introductionmentioning

confidence: 99%

Conditions Associated with Antibodies Against the Tumor-Associated Antigen MUC1 and Their Relationship to Risk for Ovarian Cancer

Cramer

Titus-Ernstoff²,

McKolanis³

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

125

117

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Many cancers, including ovarian, overexpress epithelial mucin (MUC1) and promote anti-MUC1 antibodies that may correlate with more favorable prognosis. By extension, risk for ovarian cancer might be reduced by preexisting MUC1-specific immunity. We measured anti-MUC1 antibodies in 705 control women, identified events predicting antibodies, and estimated ovarian cancer risk by comparing profiles of events generating antibodies in controls with those in 668 ovarian cancer cases. Factors predicting antibodies included oral contraceptive use, breast mastitis, bone fracture or osteoporosis, pelvic surgeries, nonuse of talc in genital hygiene, and to a lesser extent intrauterine device use and current smoking. There was a significant increase in the likelihood of having anti-MUC1 antibodies from 24.2% in women with 0 or 1 condition, to 51.4% in those with five or more conditions. By the same index of events, the risk for ovarian cancer was inversely associated with number of conditions predisposing to anti-MUC1 antibodies. Compared with having experienced 0 or 1 event, the adjusted risk for ovarian cancer decreased progressively with relative risks (

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Antibodies reactive with the protein core of MUC1 mucin are present in ovarian cancer patients and healthy women

Cited by 66 publications

References 21 publications

Inhibition of a complement regulator in vivo enhances antibody therapy in a model of mammary adenocarcinoma

Inhibition of a complement regulator in vivo enhances antibody therapy in a model of mammary adenocarcinoma

Healthy individuals have T-cell and antibody responses to the tumor antigen cyclin B1 that when elicited in mice protect from cancer

Conditions Associated with Antibodies Against the Tumor-Associated Antigen MUC1 and Their Relationship to Risk for Ovarian Cancer

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