4‐1BB ligand modulates direct and Rituximab‐induced NK‐cell reactivity in chronic lymphocytic leukemia

Abstract

NK cells play an important role in tumor immunosurveillance and largely contribute to the therapeutic success of anti-tumor antibodies like Rituximab. Here, we studied the role of the TNF family member 4-1BB ligand (4-1BBL) during the interaction of NK cells with chronic lymphocytic leukemia (CLL) cells. 4-1BBL was highly expressed on patient B-CLL cells in all 56 investigated cases. Signaling via 4-1BBL following interaction with 4-1BB, which was detected on NK cells of CLL patients but not healthy individuals, led to the release of immunoregulatory cytokines including TNF by CLL cells. CLL patient sera contained elevated levels of TNF and induced 4-1BB upregulation on NK cells, which in turn impaired direct and Rituximab-induced NK-cell reactivity against 4-1BBL-expressing targets. NK-cell reactivity was not only enhanced by blocking the interaction of NK cell-expressed 4-1BB with 4-1BBL expressed by CLL cells, but also by preventing 4-1BB upregulation on NK cells via neutralization of TNF in patient serum with Infliximab. Our data indicate that 4-1BBL mediates NK-cell immunosubversion in CLL, and thus might contribute to the reportedly compromised efficacy of Rituximab to induce NK-cell reactivity in the disease, and that TNF neutralization may serve to enhance the efficacy of Rituximab treatment in CLL.

Receptor Activator for NF-κB Ligand in Acute Myeloid Leukemia: Expression, Function, and Modulation of NK Cell Immunosurveillance

“…Although the latter may be due to contamination with RANKL-expressing healthy cells, the lack of correlation between mRNA expression and prevalence of the respective soluble and membrane-bound protein points to a potential regulatory or mutational blockade of RANKL expression by posttranscriptional and/or posttranslational mechanisms in the individual patients. This again is in line with findings on the expression and release of other TNF family members in leukemic cells (13,14,40,41).…”

“…Numerous TNF/TNFR family members are expressed by NK cells and are upregulated in malignant disease, where they influence NK reactivity upon interaction with their target cell-expressed coun- terparts (13,14,(39)(40)(41). As available data indicated that RANK can be expressed by NK cells (26), we comparatively analyzed RANK expression on NK cells of healthy donors and our AML patients.…”

Natural Killer Cell Functional Activity After 4-1BB Costimulation

“…The significant role of 4-1BB in the expansion and function of memory T cells has been investigated extensively [20]. Positive impacts of 4-1BB signal for in vitro expansion of NK cells have been demonstrated as well [16,23]. However, not all NK cell subpopulations reacted similarly against 4-1BB signal which shows the existence of a wide intrinsic threshold in NK cells against 4-1BB costimulation.…”

“…Like T cells, human and murine NK cells express 4-1BB after activation which can interact with the ligand (4-1BBL) or anti-CD137 antibodies and transduce intracellular signals [12,13]. While some studies showed negative impact of CD137 signal on cytotoxic activities or cytokine production by human or mice NK cells [13][14][15], others could demonstrate the enhancement of those activities [16][17][18]. It means that more investigations are needed to resolve the controversies about the role of 4-1BB costimulation for NK cells' function.…”

Combination Immune Therapies to Enhance Anti-Tumor Responses by NK Cells

“…Inhibiting this interaction using soluble CD137-Fc or a “blocking” anti-CD137 mAb can restore NK cell cytotoxicity (119). Taking this rationale one step further, Buechele et al suggested the potential merits of a dual strategy of blocking CD137/CD137L interaction and neutralizing immunosuppressive TNF (121). Lin et al demonstrated that human NK cells up-regulate CD137 in vitro following Fc-receptor engagement, which promotes release of pro-inflammatory cytokines but decreased cytotoxicity against K562 targets.…”