The cytotoxic potential of interleukin-15-stimulated cytokine-induced killer cells against leukemia cells

Abstract

Background aims. Cytokine-induced killer (CIK) cells may serve as an alternative approach to adoptive donor lymphocyte infusions (DLI) for patients with acute leukemia relapsing after haplo-identical hematopoietic stem cell transplantation (HSCT). We investigated the feasibility of enhancing CIK cell-mediated cytotoxicity by interleukin (IL)-15 against acute myeloid and lymphoblastic leukemia/lymphoma cells. Methods. CIK cells were activated using IL-2 (CIK_IL-2) or IL-15 (CIK_IL-15) and phenotypically analyzed by fluorescence-activated cell sorting (FACS). Cytotoxic potential was measured by europium release assay. Results. CIK_IL-2 cells showed potent cytotoxicity against the T-lymphoma cell line H9, T-cell acute lymphoblastic leukemia (T-ALL) cell line MOLT-4 and subtype M4 acute myeloid leukemia (AML) cell line THP-1, but low cytotoxicity against the precursor B (pB)-cell ALL cell line Tanoue. IL-15 stimulation resulted in a significant enhancement of CIK cell-mediated cytotoxicity against acute lymphoblastic leukemia/lymphoma cell lines as well as against primary acute myeloid and defined lymphoblastic leukemia cells. However, the alloreactive potential of CIK_IL-15 cells remained low. Further analysis of CIK_IL-15 cells demonstrated that the NKG2D receptor is apparently involved in the recognition of target cells whereas killer-cell immunoglobulin-like receptor (KIR)-HLA mismatches contributed to a lesser extent to the CIK_IL-15 cell-mediated cytotoxicity. In this context, CD3 ⁺ CD8 ⁺ CD25 ⁺ CD56^– CIK_IL-15 cell subpopulations were more effective in the lysis of AML cells, in contrast with CD56 ⁺ CIK_IL-15 cells, which showed the highest cytotoxic potential against ALL cells. Conclusions. This study provides the first evidence that CIK_IL-15 cells may offer a therapeutic option for patients with refractory or relapsed leukemia following haplo-identical HSCT.

Key Words::

• cytokine-induced killer cells
• interleukin-15
• killer-cell immunoglobulin-like receptor–HLA mismatch
• leukemia cells
• NKG2D

Acknowledgments

The authors would like to thank the ‘Hilfe für krebskranke Kinder Frankfurt e.V.’, the subproject (TP 2.1) of the ‘Translational Sarcoma Research Network’ of the Bundesministerium für Bildung und Forschung (no. 01GM0872), Germany, the Else Kröner-Fresenius-Stiftung (P65/09//A112/09), and the LOEWE Center for Cell and Gene Therapy Frankfurt funded by Hessisches Ministerium für Wissenschaft und Kunst (HMWK), funding reference number III L 4- 518/17.004 (2010), for the kind support of this work.

Disclosure of interest: The authors declare no potential conflicts of interest.