Defective antigen presentation resulting from impaired expression of costimulatory molecules in breast cancer.
Previous experiments from our laboratory have shown that immune mechanisms aiming at the destruction of tumour cells including the recognition of target cells and their elimination via the expression of intercellular adhesion molecule-1 (ICAM-1; CD54), the production of tumour necrosis factor-alpha (TNF-alpha) by monocytes and appropriate function of lymphocyte subpopulations were defective in breast cancer. Previous observations were extended to assess expression levels and regulatory mechanisms of costimulatory molecules CD54, CD80 and CD86 on monocytes derived from patients with early breast cancer (EBC). In addition, antigen presentation by antigen-presenting cells (APC) was analyzed within this context. We report that monocytes derived from patients with EBC exhibited significantly decreased expression levels of CD54 (p = 0.0002), CD80 (p = 0.009) and CD 86 (p = 0.002) compared with monocytes derived from healthy females. Simultaneously, lipopolysaccharide (LPS)-induced TNF-alpha production of monocytes was found to be defective in patients with EBC. Finally, T-cell proliferation in response to tetanus toxoid (TT) was significantly decreased in patients with EBC compared with healthy control females (p < 0.0001). Furthermore, T-cell proliferation in response to TT-pulsed APC derived from healthy controls was significantly inhibited in the presence of anti-CD54 and/or anti-CD80 antibodies in a dose-dependent manner, thus corroborating the necessity of the presence of CD54 and CD80 as costimulatory molecules in the present setting. We conclude that monocytes derived from patients with EBC showed a simultaneous defect of expression of CD54 and its regulation via TNF-alpha, CD80 and CD86 as well as T-cell proliferation following exposure to TT-pulsed APC. Based upon these findings, it is speculated that defects in costimulatory molecule expression might contribute to tolerance of the immune system towards the presence of malignant cells in patients with EBC.
Wolfram
R M
RM
Clinical Division of Oncology, University Hospital, Vienna, Austria.
Budinsky
A C
AC
Brodowicz
T
T
Kubista
M
M
Köstler
W J
WJ
Kichler-Lakomy
C
C
Hellan
M
M
Kahlhammer
G
G
Wiltschke
C
C
Zielinski
C C
CC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017951:Antigen Presentation; D015703:Antigens, CD / Q000097:blood; D001943:Breast Neoplasms / Q000097:blood / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000097:blood*; D008213:Lymphocyte Activation; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D009367:Neoplasm Staging; D011994:Recombinant Proteins / Q000494:pharmacology; D012016:Reference Values; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000494:pharmacology
D015703:Antigens, CD; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1