CIRCULATING MICA PROTEIN IN PATIENTS WITH MALIGNANT LYMPHOMAS

Abstract

MICA is a stress-induced protein that, as a rule, is not expressed in healthy tissues, but appears in large amounts on the surface of cells undergoing malignant transformation. In humans, this protein can either initiate antitumor immune response, or facilitate tumor cells for their escape of destruction. After shedding from tumor cell surface, soluble MICA enters blood circulation and contributes to decreased activity of effector cells, due to inactivation of NKG2D receptor. The aim of our study was to determine differences in circulating sMICA concentrations in sera of patients with different types of malignant lymphomas, and to evaluate the impact of sMICA upon NKG2D-positive cytotoxic lymphocytes. In experimental models with C1R-MICA cells, the MICA shedding was shown to occur from the surface of cultured tumor cells into the extracellular space. A reduced NKG2D expression dependent on sMICA concentration in the culture medium was demonstrated by flow cytometry in peripheral mononuclear cells, thus suggesting a role of serum sMICA in suppression of antitumor immune response. The sMICA detection was performed in patients with various types of B- or T-cell non-Hodgkin’s lymphomas by means of enzyme-linked immunosorbent assay. The groups of patients with increased sMICA content were identified and compared with the control group. Minimal amounts of serum sMICA were registered in the control group, with the median of 20 pg/ml. In a combined group of patients with various B-cell lymphomas, an increase in circulating sMICA amounts was shown, at the levels of more than 6.5 times exceeding the control values. The highest values of sMICA were recorded among the patients with chronic lymphocytic leukemia, diffuse large cell lymphoma, and multiple myeloma. Maximal sMICA levels among the investigated groups of patients were observed in the group of patients with T-cell anaplastic lymphoma (median of 574 pg/ml). The study provides preliminary evidence for a suppressive effect of different (immuno)chemotherapy components, in particular, rituximab and radiation therapy, upon serum sMICA contents in the lymphoma patients. Thus, elevated serum sMICA levels in patients with hematological malignancies may be considered as an additional criterion for application of the antitumor therapy. sMICA monitoring at different stages of cytostatic treatment may be useful in order to evaluate its efficiency.

Keywords

• malignant lymphomas
• lymphoproliferative diseases
• mica protein
• smica
• cytotoxic lymphocytes
• nkg2d receptor