Trogocytosis in Multiple Myeloma.

Abstract Trogocytosis is the transfer of cell membrane material from one cell to another during short term cell-cell contact. Recent studies have suggested that the transfer of cell membrane patches across the immunological synapse is at least partly responsible for immune tolerance, tumor escape and the production of adaptive T regulatory cells (Tregs). We sought to identify the extent of tumor-related trogocytosis in patients with multiple myeloma and have developed an in vitro model for further study. Trogocytosis in patients with multiple myeloma was demonstrated by flow cytometry, immunohistochemistry, confocal microscopy, lack of mRNA expression and by the failure to upregulate costimulatory molecules in vitro after stimulation by IL2 and huCD40LT. Of the costimulatory molecules CD80, CD86, B7-H1, B7-H3 and PD-L2, only CD80 and CD86 showed significant transfer to T cells. Increased CD80 expression was found on the T cells of 9% of patients and CD86 on 13% of patients (n= 95). Both CD4 and CD8 memory (CD45RO+) cells were involved but not naïve T cells (CD45RA+). HLA-G expression was found on less than 1% of T cells in 69/70 different myeloma blood samples. Following biotinylation of plasma cells (CD38++) using an in vitro culture model, trogocytosis was demonstrated in up to 36% of T cells. The presence of trogocytosis on CD3- TCRαβ-mutant Jurkat cells (J.RT3-T3.3) and on normal T cells with HLA incompatibility infers that trogocytosis is independent of immune recognition and TCR engagement. In vitro stimulation with IL-2 and huCD40LT and mRNA studies showed that T cells acquire CD80 and CD86 cell surface antigen but unlike B cells do not produce CD80 and CD86 mRNA (n=5) and cannot be stimulated to express CD80 and CD86 (n=6). Trogocytosis was not evident in age-matched control lymphocytes but could be induced in normal lymphocytes in vitro after exposure to malignant plasma cells. Trogocytosis is common in patients with multiple myeloma and involves the transfer of costimulatory molecules and other cell membrane proteins from malignant plasma cells to T cells. Tumor-induced trogocytosis may be a common cause of the failure of cytotoxic T cells and provide a mechanism of tumor escape.