Primary Immunoprevention of Epithelial Ovarian Carcinoma by Vaccination against the Extracellular Domain of Anti-Müllerian Hormone Receptor II

Abstract

Epithelial ovarian carcinoma (EOC) is the most prevalent form of ovarian cancer in the United States, representing approximately 85% of all cases and causing more deaths than any other gynecologic malignancy. We propose that optimized control of EOC requires the incorporation of a vaccine capable of inducing safe and effective preemptive immunity in cancer-free women. In addition, we hypothesize that ovarian-specific self-proteins that are "retired" from autoimmune-inducing expression levels as ovaries age but are expressed at high levels in emerging EOC may serve as vaccine targets for mediating safe and effective primary immunoprevention. Here, we show that expression of the extracellular domain of anti-Müllerian hormone receptor II (AMHR2-ED) in normal tissues is confined exclusively to the human ovary, drops to nonautoimmune inducing levels in postmenopausal ovaries, and is at high levels in approximately 90% of human EOC. We found that AMHR2-ED vaccination significantly inhibits growth of murine EOC and enhances overall survival without inducing oophoritis in aged female mice. The observed inhibition of EOC growth was mediated substantially by induction of AMHR2-ED-specific IgG antibodies that agonize receptor signaling of a Bax/caspase-3-dependent proapoptotic cascade. Our results indicate that AMHR2-ED vaccination may be particularly useful in providing safe and effective preemptive immunity against EOC in women at high genetic or familial risk who have the greatest need for a preventive vaccine and ultimately in cancer-free postmenopausal women who account for 75% of all EOC cases. .

Exosomes from GM-CSF expressing embryonic stem cells are an effective prophylactic vaccine for cancer prevention

“…A recent report by Dr. Tuohy's group showed that targeting the extracellular domain of anti-Mullerian hormone receptor II (AMHR2-ED) is an effective strategy for immunoprevention of ovarian cancer. 48 AMHR2-ED is a so-called "retired antigen" that is required for tissue-specific functions and its expression decreases with aging. 48,49 Similar to testisassociated antigens (e.g.…”

“…48 AMHR2-ED is a so-called "retired antigen" that is required for tissue-specific functions and its expression decreases with aging. 48,49 Similar to testisassociated antigens (e.g. NY-ESO-1), AMHR2-ED antigen is specifically overexpressed in ovarian cancer cells but shows limited expression in normal tissues and hence forms an appealing target for ovarian cancer vaccine development with minimal risk for inducing autoimmunity.…”

“…NY-ESO-1), AMHR2-ED antigen is specifically overexpressed in ovarian cancer cells but shows limited expression in normal tissues and hence forms an appealing target for ovarian cancer vaccine development with minimal risk for inducing autoimmunity. 48,49 Another such example of a "retired antigen" is alphalactalbumin which is a breast-specific differentiation protein conditionally expressed in high levels in breast carcinomas only during lactation. 50 Tuohy and colleagues reported that immunoreactivity against alpha-lactalbumin provides protection against the growth of breast tumors without any detectable inflammation in normal non-lactating breast tissue.…”

Ovarian Cancer Stem Cells with High ROR1 Expression Serve as a New Prophylactic Vaccine for Ovarian Cancer

“…Epithelial ovarian carcinoma (EOC) is the most prevalent form of ovarian cancer, causing more deaths than any other gynecologic malignancy [1, 2]. At present, the mainstay of EOC treatment consists of cytoreductive surgery and platinum-based chemotherapy.…”

Vaccination with induced pluripotent stem cells confers protection against cancer

“…This gene signature was most prevalent in estrogen receptor negative breast cancer patients who generally fail to respond to hormonal therapies used for treating breast cancer (5). Recent studies by Tuohy's group have shown that immunotherapeutic targeting of certain "retired antigens" can be effective in prevention of ovarian and breast cancers (7,8). Examples of such antigens include the extracellular domain of anti-Mullerian hormone receptor II (AMHR2-ED) and α-lactalbumin proteins; both of these are overexpressed in cancer cells but show limited expression in normal tissues and hence are attractive targets for prophylactic cancer vaccine with minimal risk for inducing toxicity (7,8).…”