Aromatase inhibitors increase the sensitivity of human tumor cells to monocyte-mediated, antibody-dependent cellular cytotoxicity.
OBJECTIVE
A randomized, placebo-controlled phase III trial of the breast cancer vaccine Theratope (Biomira Corporation, Edmonton, Alberta, Canada), which expresses the underglycosylated, mucin-associated peptide STn showed that patients treated concomitantly with hormone therapy plus vaccine survived significantly longer than patients treated with hormone therapy plus a control vaccine. The objective of this study was to elucidate a mechanism to explain this effect.


METHODS
Tumor cells characterized for expression of estrogen receptor (ER), STn, and Mucin-1 (Muc1) were pretreated (24 hours) with the aromatase inhibitor (AI) formestane, followed by assessment of sensitivity to monocyte-mediated killing in the presence and absence of STn or Muc1 antibodies (Abs) using the (51)Cr-release assay.


RESULTS
ER+/STn+/Muc1+ tumor cells cultured in medium were equally sensitive to killing by monocytes in the absence or presence of STn and Muc1 Abs (mean = 54% and 55% cytolysis, respectively, P = not significant). Formestane-pretreated cells showed decreased sensitivity to killing by monocytes in the absence of Abs (mean = 45% cytolysis, P = .07) but significantly increased sensitivity to monocyte-mediated, antibody-dependent cellular cytotoxicity (MM-ADCC) (mean = 65%, P = .003). These effects were not seen with either ER+/STn-/Muc1+ cells or ER-/STn+/Muc1+ cells, indicating the need for both ER and STn positivity of the target tumor cells.


CONCLUSIONS
Tumor cells treated with an AI exhibit increased sensitivity to MM-ADCC. The capacity of an AI to "sensitize" tumor cells to this form of antitumor immunity represents a heretofore, undescribed mechanism whereby a hormone-based treatment may collaborate with antigen-specific tumor immunity to produce improved tumor control in vivo in metastatic breast cancer patients.
Braun
Donald P
DP
Cancer Institute, 3120 Glendale Avenue, Toledo, OH 43614, USA. dbraun@mco.edu
Crist
Keith A
KA
Shaheen
Fehr
F
Staren
Edgar D
ED
Andrews
Stephen
S
Parker
Joanne
J
D000735:Androstenedione / Q000031:analogs & derivatives* / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects* / Q000276:immunology; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms; D018797:Cell Cycle Proteins / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D009000:Monocytes / Q000276:immunology; D018396:Mucin-1 / Q000276:immunology; D010051:Ovarian Neoplasms; D020648:Peptide Elongation Factor 1; D011960:Receptors, Estrogen / Q000276:immunology
D047072:Aromatase Inhibitors; D018797:Cell Cycle Proteins; C503234:EEF1A2 protein, human; D018396:Mucin-1; D020648:Peptide Elongation Factor 1; D011960:Receptors, Estrogen; D000735:Androstenedione; C014594:formestane