Unlicensed NK cells target neuroblastoma following anti-GD2 antibody treatment

Department of Pediatrics, Sloan-Kettering Institute, New York, NY 10065, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 08/2012; 122(9):3260-70. DOI: 10.1172/JCI62749
Source: PubMed


Survival outcomes for patients with high-risk neuroblastoma (NB) have significantly improved with anti-disialoganglioside GD2 mAb therapy, which promotes NK cell activation through antibody-dependent cell-mediated cytotoxicity. NK cell activation requires an interaction between inhibitory killer cell immunoglobulin-like receptors (KIRs) and HLA class I ligands. NK cells lacking KIRs that are specific for self HLA are therefore "unlicensed" and hyporesponsive. mAb-treated NB patients lacking HLA class I ligands for their inhibitory KIRs have significantly higher survival rates, suggesting that NK cells expressing KIRs for non-self HLA are mediating tumor control in these individuals. We found that, in the presence of mAb, both licensed and unlicensed NK cells are highly activated in vitro. However, HLA class I expression on NB cell lines selectively inhibited licensed NK cell activity, permitting primarily unlicensed NK cells to mediate antibody-dependent cell-mediated cytotoxicity. These results indicate that unlicensed NK cells play a key antitumor role in patients undergoing mAb therapy via antibody-dependent cell-mediated cytotoxicity, thus explaining the potent "missing KIR ligand" benefit in patients with NB.

Download full-text


Available from: Nidale Tarek, May 05, 2015
26 Reads
  • Source
    • "Anti-TACA antibodies, thus, may be involved in more than direct tumor cytotoxicity even though this mechanism is exciting. Although, the exact mechanism may represent a cascade of steps that are still to be established, TACA targeting has the potential to yield anti-tumor effects mediated by Natural Killer cells, which has not been thoroughly investigated in humans even though there is some evidence of therapeutic benefit (118, 119) or through neutralization of tumor immunosuppressive factors in the form of soluble gangliosides (120–122). Future work should clarify the points of involvement of antibody/carbohydrate interactions in modulating tumor growth and facilitating innate surveillance mechanisms. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Molecular mimicry is fundamental to biology and transcends to many disciplines ranging from immune pathology to drug design. Structural characterization of molecular partners has provided insight into the origins and relative importance of complementarity in mimicry. Chemical complementarity is easy to understand; amino acid sequence similarity between peptides, for example, can lead to cross-reactivity triggering similar reactivity from their cognate receptors. However, conformational complementarity is difficult to decipher. Molecular mimicry of carbohydrates by peptides is often considered one of those. Extensive studies of innate and adaptive immune responses suggests the existence of carbohydrate mimicry, but the structural basis for this mimicry yields confounding details; peptides mimicking carbohydrates in some cases fail to exhibit both chemical and conformational mimicry. Deconvolution of these two types of complementarity in mimicry and its relationship to biological function can nevertheless lead to new therapeutics. Here, we discuss our experience examining the immunological aspects and implications of carbohydrate-peptide mimicry. Emphasis is placed on the rationale, the lessons learned from the methodologies to identify mimics, a perspective on the limitations of structural analysis, the biological consequences of mimicking tumor-associated carbohydrate antigens, and the notion of reverse engineering to develop carbohydrate-mimetic peptides in vaccine design strategies to induce responses to glycan antigens expressed on cancer cells.
    Frontiers in Immunology 06/2014; 5:308. DOI:10.3389/fimmu.2014.00308
  • Source
    • "However, in a process termed licensing, the NK cells that do not recognize self-MHC I become “anergic,” thus ensuring self-tolerance (48). Strikingly, it has been recently shown that the “anergic” NK cells that do not recognize self can become activated during inflammatory conditions and are more efficient in clearing infections or tumor cells than the licensed NK cells (49–51). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Human maternal autoantibodies can trigger autoimmune diseases such as congenital heart block (CHB) in the progeny of women with lupus or Sjogren's disease. The pathogenic effect of early autoantibody (autoAb) exposure has been investigated in a murine neonatal autoimmune ovarian disease (nAOD) model triggered by a unique ZP3 antibody. Although immune complexes (IC) are formed in adult and neonatal ovaries, ZP3 antibody triggers severe nAOD only in <7-day-old neonatal mice. Propensity to nAOD is due to the uniquely hyper-responsive neonatal natural killer (NK) cells that lack the inhibitory Ly49C/I receptors. In nAOD, the neonatal NK cells directly mediate ovarian inflammation and oocyte depletion while simultaneously promoting de novo pathogenic ovarian-specific T cell responses. Resistance to nAOD in older mice results from the emergence of the Ly49C/I(+) NK cells that regulate effector NK cells and from CD25(+) regulatory T cell control. In preliminary studies, FcγRIII(+) NK cells as well as the ovarian resident FcγRIII(+) macrophages and/or dendritic cells were found to be as indispensable players. Activated by ovarian IC, they migrate to lymphoid organs where NK cell priming occurs. Remarkably, the findings in nAOD are very similar to those reported for neonatal responses to a retrovirus and its cognate antibody that lead to long-lasting immunity. Studies on nAOD therefore provide insights into maternal autoAb-mediated neonatal autoimmunity, including CHB, while simultaneously uncovering new properties of the neonatal innate and adaptive responses, lethality of premature infant infection, and novel neonatal antiviral vaccine design.
    Frontiers in Immunology 05/2014; 5:242. DOI:10.3389/fimmu.2014.00242
  • Source
    • "For example, anti-GD2 antibody-treated NB patients lacking HLA class I ligands for their inhibitory killer cell immunoglobulin-like receptors have significantly higher survival rates than those with HLA class I ligands. Unlicensed NK cells are thought to be responsible for this phenomenon [16]. If tumorspheres are obtained from every patient regardless of tumor status, i.e., primary or metastatic, high risk or low risk and high grade or low grade, those are precious resources for evaluating the efficacy of the treatment prior to its clinical use. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumorsphere culture enriches and expands tumor cells, thus providing important resources for cancer studies. However, as compared with metastatic tissues, primary tumors in the nervous system rarely give rise to long-surviving tumorspheres, thereby seriously limiting studies on these cancers. This might be due to the limited self-renewal capability of tumor cells and/or to inappropriate culture conditions. The growth and maintenance of tumor cells may depend on microenvironments and/or cell origins (e.g., primary or metastatic; stem cell-like or progenitor-like). Here, we attempted to establish a tumorsphere culture condition for primary neuroblastoma (NB). Primary tumors in MYCN transgenic mice, a NB model, could be serially transplanted, suggesting that these tumors contain cells with a high self-renewal potential. However, primary tumors did not give rise to tumorspheres under a serum-free neurosphere culture condition. The newly established culture condition (named PrimNeuS) contained two critical ingredients: fetal bovine serum and β-mercaptoethanol were essential for tumorsphere formation as well as indefinite passages. The spheres could be passaged more than 20 times without exhaustion under this condition, exhibited a property of differentiation and formed tumors in vivo. Unexpectedly, PrimNeuS revealed that the MYCN transgenic mice had bone marrow metastasis. Furthermore, subcutaneous tumors derived from tumorspheres of primary tumors showed bone marrow metastasis. Taken together, PrimNeuS provides resources for the study of NB and can be used as a powerful tool for the detection of minimal residual disease and for in vitro evaluation prior to personalized therapy.
    PLoS ONE 01/2014; 9(1):e86813. DOI:10.1371/journal.pone.0086813 · 3.23 Impact Factor
Show more