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Trop-2 Overexpression in Poorly Differentiated Endometrial Endometrioid Carcinoma: Implications for Immunotherapy With hRS7, a Humanized Anti–Trop-2 Monoclonal Antibody
  1. Eliana Bignotti, PhD*,
  2. Antonella Ravaggi, PhD*,
  3. Chiara Romani, MS*,
  4. Marcella Falchetti, MD,
  5. Silvia Lonardi, MD,
  6. Fabio Facchetti, MD,
  7. Sergio Pecorelli, MD*,
  8. Joyce Varughese, MD,
  9. Emiliano Cocco, PhD,
  10. Stefania Bellone, PhD,
  11. Peter E. Schwartz, MD,
  12. Thomas J. Rutherford, MD, PhD and
  13. Alessandro D. Santin, MD
  1. * Angelo Nocivelli Institute of Molecular Medicine, Division of Gynecologic Oncology and
  2. Department of Pathology, University of Brescia, Brescia, Italy; and
  3. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT.
  4. Radiation Oncology and
  5. § Obstetrics/Gynecology Division of Gynecologic Oncology, Case Comprehensive Cancer Center, University Hospitals Case Medical Center and Case Western Reserve School of Medicine, Cleveland, OH; and
  6. Department of Gynecologic Oncology, University of Turin, Mauriziano “Umberto I” Hospital, Turin, Italy.
  1. Address correspondence and reprint requests to Alessandro D. Santin, MD, Department of Obstetrics, Gynecology & Reproductive Sciences, Room 305 LSOG, Yale University School of Medicine, 333 Cedar St, PO Box 208063, New Haven, CT 06520-8063. E-mail: alessandro.santin{at}yale.edu.

Abstract

Objective We evaluated the expression of human trophoblast cell surface marker (Trop-2) in endometrial endometrioid carcinoma (EEC) and the potential application of hRS7, a humanized monoclonal anti–Trop-2 antibody, as a therapeutic agent against poorly differentiated EEC.

Methods Trop-2 expression was evaluated by immunohistochemistry in 131 EEC with different degrees of differentiation and 32 normal endometrial controls (NEC). Trop-2 expression was also evaluated by quantitative real-time polymerase chain reaction and flow cytometry in 3 primary EEC cell lines derived from patients harboring poorly differentiated EEC. Finally, the sensitivity of grade 3 EEC cell lines to hRS7 antibody-dependent cellular cytotoxicity was tested in standard 5-hour 51Cr release assays.

Results Trop-2 expression was detected in 126 (96.2%) of 131 EEC samples. Tumor tissues showed markedly increased Trop-2 positivity compared with NEC (P = 0.001). Trop-2 expression was significantly higher in all grades of EEC versus NEC. Grade 3 tumors displayed significantly stronger Trop-2 immunostaining compared with grade 1 EEC (P = 0.01). High Trop-2 expression by quantitative real-time polymerase chain reaction and flow cytometry was found in 1 grade 3 EEC primary cell line (EEC-ARK-1). Unlike Trop-2–negative EEC cell lines, EEC-ARK-1 was found highly sensitive to hRS7-mediated antibody-dependent cellular cytotoxicity in vitro (range of killing, 33.9%–50.6%; P = 0.004). Human serum did not significantly inhibit hRS7-mediated cytotoxicity against EEC-ARK-1 (P = 0.773).

Conclusions Trop-2 is highly expressed in EEC, and its expression is significantly higher in poorly differentiated EEC when compared with well-differentiated EEC. Primary grade 3 EECs overexpressing Trop-2 are highly sensitive to hRS7-mediated cytotoxicity in vitro. hRS7 may represent a novel therapeutic agent for the treatment of high-grade EEC refractory to standard treatment modalities.

  • Endometrial cancer
  • Endometrioid carcinoma
  • Immunotherapy
  • Natural killer cells
  • Trop-2 protein

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Footnotes

  • The authors have no conflicts of interest to disclose.

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