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 targ et cells and their elimination via the expression of intercellular adhesion molecule-I (ICAM-I; CD54), the production of tumour necrosis factor-alpha (TNF-alpha) by monocytes and appropriate function of lymphocyte subpopulati ons were defective in breast cancer. Previous observations were extended to assess expression levels and regulatory mechanisms of costimulatory molecu les CD54, CD80 and CD86 on monocytes derived from patients with early breas t cancer (EBC). In addition, antigen presentation by antigen-presenting cel ls (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 toroid (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 i nhibited 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 th at 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 th ese findings, it is speculated that defects in costimulatory molecule expre ssion might contribute to tolerance of the immune system towards the presen ce of malignant cells in patients with EBC, Int. J. Cancer 88:239-244, 2000 . (C) 2000 Wiley-Liss, Inc.