CD86+ or HLA-G+ can be transferred via trogocytosis from myeloma cells to T cells and are associated with poor prognosis

Abstract

The transfer of membrane proteins between cells during contact, known as trogocytosis, can create novel cells with a unique phenotype and altered function. We demonstrate that trogocytosis is more common in multiple myeloma (MM) than chronic lymphocytic leukemia and Waldenstrom macroglobulinaemia; that T cells are more probable to be recipients than B or natural killer cells; that trogocytosis occurs independently of either the T-cell receptor or HLA compatibility; and that after trogocytosis, T cells with acquired antigens can become novel regulators of T-cell proliferation. We screened 168 patients with MM and found that CD86 and human leukocyte antigen G (HLA-G) were antigens commonly acquired by T cells from malignant plasma cells. CD3+CD86acq+ and CD3+ HLA-Gacq+ cells were more prevalent in bone marrow than peripheral blood samples. The presence of either CD86 or HLA-G on malignant plasma cells was associated with a poor prognosis. CD38++ side population cells expressed HLA-G, suggesting that these putative myeloma stem cells could generate immune tolerance. HLA-G+ T cells had a regulatory potency similar to natural Tregs, thus providing another novel mechanism for MM to avoid effective immune surveillance.

A controversy on HLA-G and B-cell malignancies?

“…Moreover, MM are transformed terminally maturated B-cells and as such expressed ILT2 in BM and blood. However, despite this ILT2 expression, there are discrepancies in the reports on the function of HLA-G on MM, ranging from "indicative of bad prognosis" [8] to "irrelevant to prognosis" [13,14]. This indicates that ILT2 expression is not sufficient to explain the data discrepancies observed for the function of HLA-G on B-cell malignancies.…”

“…Here, HLA-G expression correlated with the number of regulatory T-cells (Tregs) [6] and is involved in the protection of B-CLL cells from NK-mediated killing [6,7]. In multiple myeloma (MM) HLA-G expression on malignant plasma cells was also associated with a poor prognosis [8]. Interestingly, HLA-G was frequently acquired by T-cells from malignant plasma cells through a mechanism of membrane transfer.…”

Human HLA-G+ extravillous trophoblasts: Immune-activating cells that interact with decidual leukocytes

“…HLA-E and HLA-G have been shown to limit NK cytotoxicity (10,11). HLA-G-expressing cells also have been shown to increase the secretion of cytokines such as interleukin-6 (IL-6) and IL-8 (6,12,13), to induce regulatory T cells (Treg) (14), and to modulate antigen-presenting cells by binding to the HLA-G receptor Leukocyte Ig-like receptor subfamily B member 1 (LILBR1, also known as ILT2) (13,15). At term, pregnancy allogeneic paternal HLA-C expressed on EVT was correlated with maternal dT activation and induction of fetus-specific Treg (16).…”

The HLA-G cycle provides for both NK tolerance and immunity at the maternal–fetal interface

“…HLA-G acts mainly to prevent NK cell cytotoxicity (4-6) and T-cell cytotoxicity (7) and induce tolerance (8,9). The maternal-fetal interface is a unique tolerized immune compartment.…”