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B-lymphoma cells escape rituximab-triggered elimination by NK cells through increased HLA class I expression.
Exp Hematol 2010; 38(3):213-21EH

Abstract

OBJECTIVE

Antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells is a major effector mechanism of the monoclonal anti-CD20 antibody rituximab in eliminating B-cell lymphomas. Resistance to this treatment occurs, although CD20 antigen is expressed on the tumor cells.

MATERIALS AND METHODS

A model of ADCC was established by stimulating human bulk NK cells and inhibitory killer immunoglobulin receptor (KIR)-defined NK cells from human leukocyte antigen (HLA)-typed donors. NK-cell activation was triggered via stimulation of the Fc receptor with immunoglobulin G aggregates, rituximab-labeled HLA-defined CD20-positive B-lymphoblast cell lines or CD20-positive B-lymphoma cell lines. The effect of KIR ligation by anti-KIR antibodies and HLA, the HLA expression density and rituximab concentrations on the efficacy of ADCC were analyzed in granzyme B ELISPOT measuring NK-cell activation and fluorescein-activated cell sorting cytotoxicity assay.

RESULTS

HLA, but not CD20 expression density correlated with NK-cell activity against rituximab-labeled targets. ADCC was increased or decreased following HLA shielding or KIR activation by anti-KIR antibodies, respectively. Herein we show that rituximab-induced ADCC is attenuated upon ligation of KIR by HLA molecules expressed on human B-lymphoma target cells. Moreover, anti-KIR antibodies do not only block KIR/HLA interactions, but display agonistic effects at the KIR, which has to be considered for therapeutical applications.

CONCLUSION

KIR activation and HLA expression density are critical determinants for the efficacy of rituximab treatment. An explanation for the failure of rituximab treatment may be the protection of the tumor cells from ADCC by inhibiting NK-cell function with their surface HLA.

Authors+Show Affiliations

Department of Haematology and Oncology, Georg-August University of Göttingen, Göttingen, Germany. a.borgerding@med.uni-goettingen.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20056126

Citation

Borgerding, Andrea, et al. "B-lymphoma Cells Escape Rituximab-triggered Elimination By NK Cells Through Increased HLA Class I Expression." Experimental Hematology, vol. 38, no. 3, 2010, pp. 213-21.
Borgerding A, Hasenkamp J, Engelke M, et al. B-lymphoma cells escape rituximab-triggered elimination by NK cells through increased HLA class I expression. Exp Hematol. 2010;38(3):213-21.
Borgerding, A., Hasenkamp, J., Engelke, M., Burkhart, N., Trümper, L., Wienands, J., & Glass, B. (2010). B-lymphoma cells escape rituximab-triggered elimination by NK cells through increased HLA class I expression. Experimental Hematology, 38(3), pp. 213-21. doi:10.1016/j.exphem.2009.12.007.
Borgerding A, et al. B-lymphoma Cells Escape Rituximab-triggered Elimination By NK Cells Through Increased HLA Class I Expression. Exp Hematol. 2010;38(3):213-21. PubMed PMID: 20056126.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - B-lymphoma cells escape rituximab-triggered elimination by NK cells through increased HLA class I expression. AU - Borgerding,Andrea, AU - Hasenkamp,Justin, AU - Engelke,Michael, AU - Burkhart,Nina, AU - Trümper,Lorenz, AU - Wienands,Jürgen, AU - Glass,Bertram, Y1 - 2010/01/06/ PY - 2009/10/06/received PY - 2009/12/11/revised PY - 2009/12/28/accepted PY - 2010/1/9/entrez PY - 2010/1/9/pubmed PY - 2010/4/24/medline SP - 213 EP - 21 JF - Experimental hematology JO - Exp. Hematol. VL - 38 IS - 3 N2 - OBJECTIVE: Antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells is a major effector mechanism of the monoclonal anti-CD20 antibody rituximab in eliminating B-cell lymphomas. Resistance to this treatment occurs, although CD20 antigen is expressed on the tumor cells. MATERIALS AND METHODS: A model of ADCC was established by stimulating human bulk NK cells and inhibitory killer immunoglobulin receptor (KIR)-defined NK cells from human leukocyte antigen (HLA)-typed donors. NK-cell activation was triggered via stimulation of the Fc receptor with immunoglobulin G aggregates, rituximab-labeled HLA-defined CD20-positive B-lymphoblast cell lines or CD20-positive B-lymphoma cell lines. The effect of KIR ligation by anti-KIR antibodies and HLA, the HLA expression density and rituximab concentrations on the efficacy of ADCC were analyzed in granzyme B ELISPOT measuring NK-cell activation and fluorescein-activated cell sorting cytotoxicity assay. RESULTS: HLA, but not CD20 expression density correlated with NK-cell activity against rituximab-labeled targets. ADCC was increased or decreased following HLA shielding or KIR activation by anti-KIR antibodies, respectively. Herein we show that rituximab-induced ADCC is attenuated upon ligation of KIR by HLA molecules expressed on human B-lymphoma target cells. Moreover, anti-KIR antibodies do not only block KIR/HLA interactions, but display agonistic effects at the KIR, which has to be considered for therapeutical applications. CONCLUSION: KIR activation and HLA expression density are critical determinants for the efficacy of rituximab treatment. An explanation for the failure of rituximab treatment may be the protection of the tumor cells from ADCC by inhibiting NK-cell function with their surface HLA. SN - 1873-2399 UR - https://www.unboundmedicine.com/medline/citation/20056126/B_lymphoma_cells_escape_rituximab_triggered_elimination_by_NK_cells_through_increased_HLA_class_I_expression_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0301-472X(09)00488-3 DB - PRIME DP - Unbound Medicine ER -