NK resistance of tumor cells from multiple myeloma and chronic lymphocytic leukemia patients: implication of HLA-G

Abstract

Exploiting the antitumor effect of natural killer (NK) cells has regained interest in light of data from preclinical and clinical work on the potential of alloreactive NK cells. Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) represent the two most prevalent adult hematological malignancies in the western hemisphere. To evaluate the role of NK cells in the immune surveillance and their therapeutic potential for CLL and MM, tumor cell susceptibility to NK-mediated killing was investigated. Results show relative resistance of tumor cells from CLL as well as MM (73 and 70% of the patients, respectively) to NK-mediated killing. To gain insight into molecular mechanisms of this resistance, the expression of the tolerogenic HLA-G molecule in CLL and MM and its relevance to susceptibility to NK-mediated killing were investigated. HLA-G transcript was found in tumor cells from 89% (n ¼ 19) of CLL and 100% (n ¼ 9) of MM patients examined. HLA-G1 surface expression was observed in CLL and was very low or undetectable in MM. Notably, blocking of HLA-G1 with specific antibody on CLL samples increased their susceptibility to NK-mediated killing, demonstrating that HLA-G participates in protecting CLL cells from NK-mediated killing and may thus contribute to their immune escape in vivo.

Immune recovery after fludarabine–cyclophosphamide–rituximab treatment in B-chronic lymphocytic leukemia: implication for maintenance immunotherapy

“…First, it is conceivable that host immune function may contribute to the control of the disease; for example, B-CLL relapse reflects escape to innate immunity through proper deficit in natural killer (NK) or Tgd cell function, which can be further worsened by treatment. [6][7][8] Second, in the perspective of maintenance therapy with monoclonal antibodies, 9 including rituximab (RTX), it is important to know whether antibody-dependent cellular cytotoxicity (ADCC) capacity of natural effector cells is preserved during the post-FCR period. For this reason, we have measured at different times immune cell counts (NK, CD4, CD8, Tgd), in vitro nonleukemic peripheral blood lymphocyte (PBL) cytotoxicity with or without interleukin (IL)-2, reflecting NK and lymphokine activated killer (LAK) function, respectively, as well as RTX-dependent PBL ADCC against autologous leukemic cells.…”

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

“…As shown for B-CLL and ALL, HLA-G may protect the tumor cells by blocking immune effectors, decreasing the absolute T-and NK-cell counts or inducing Treg. For therapeutic intervention, patients with B-cell malignancies would benefit from a blocking of HLA-G functions to restore anti-tumor immunity, as recently demonstrated [7]. For other B-cell malignancies, however, HLA-G expression does not directly correlate with worse prognosis.…”

“…Patients having this genotype revealed a reduced overall survival [6]. 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].…”

“…There is no data on HLA-G or ILT2 expression by tissue CLL. However, if tissue CLL cells express HLA-G but not ILT2, HLA-G would inhibit T-or NK-cells exactly as evidenced recently [6,7]. In this configuration, the overall effect of HLA-G would indeed impair the anti-tumor response, and a correlation between HLA-G presence and bad prognosis would be observed.…”

Mono- and dual-targeting triplebodies activate natural killer cells and have anti-tumor activityin vitroandin vivoagainst chronic lymphocytic leukemia

“…Complete remissions in HSCT are achieved through the graft versus leukemia (GvL) effect 5 mediated mainly by NK cells. 6 NK cells utilize sets of "activating" and "inhibitory" receptors to sense various kinds of danger signals. 7,8 The major activating receptors on NK cells include FcgRIIIa (CD16a), NKG2D and the natural cytotoxicity receptors (NCRs) such as NKp30, NKp44 and NKp46.…”