CD137 ligand signalling induces differentiation of primary acute myeloid leukaemia cells

Abstract

SummaryCD137 ligand (CD137L), a member of the tumour necrosis factor family, is expressed as a cell surface molecule. Engagement of CD137L on haematopoietic progenitor cells induces monocytic differentiation, and in peripheral monocytes CD137L signalling promotes differentiation to mature dendritic cells. We hypothesized that CD137L signalling would also induce differentiation in transformed myeloid cells. Here we show that recombinant CD137 protein, which crosslinks CD137L and initiates reverse CD137L signalling in myeloid cells, induces morphological changes (adherence, spreading), loss of progenitor markers (CD117), expression of maturation markers (CD11b, CD13) and secretion of cytokines that are indicative of myeloid differentiation. Under the influence of CD137L signalling, acute myeloid leukaemia (AML) cells acquired expression of co-stimulatory molecules (CD80, CD86, CD40), the dendritic cell marker CD83 and dendritic cell activities, enabling them to stimulate T cells. CD137L signalling induced differentiation in 71% (15 of 21) of AML samples, irrespective of French-American-British classification and CD137L expression level. However, the type of response varied with the AML subtype and patient sample. In summary, this study demonstrated that CD137L signalling induced differentiation in malignant cells of AML patients, and suggests that it may be worthwhile to investigate treatment with recombinant CD137 protein as a potential novel therapeutic approach for AML.

Expression of 4-1Bb and Its Ligand on Blasts Correlates with Prognosis of Patients with Aml

“…In previous studies, we revealed that the release of so4-1BBL from AML-blast samples leads to a higher plasma level and expression correlated with prognostically adverse AML subtypes what might be explained by a binding of so4-1BBL to T-cells, thereby inhibiting T-cell-c4-1BB binding to tumor cells. Moreover, c4-1BBL is known to be expressed on AML blasts’ surface8 and was stated to have an impact in the blasts’ maturation processes due to its reverse signaling capability when stimulated as shown in 15 of 21 not closer specified AML samples in a study of Cheng et al 30 that could not be confirmed in our study, probably due to a different composition of our pt cohort. In cut-off analyses, we correlated significantly higher 4-1BBL expression with shorter (but not significant) DFS and OS times, thereby providing evidence of correlation not only of a higher so4-1BBL release but also of a higher c4-1BBL expression in the case of unfavorable prognosis.…”

CD137 and CD137L signals are main drivers of type 1, cell-mediated immune responses

“…56 Another study demonstrated reverse CD137L signaling into AML cells induces differentiation, resulting in reduced proliferation, and suggested this approach to be explored as a novel differentiation therapy for AML. 57 In summary, the data from the role of CD137 and CD137L in cancer further support the notion of CD137-CD137L interaction promoting type 1, cell-mediated immune responses.…”

TNFSF9 exerts an inhibitory effect on hepatocellular carcinoma

“…Recombinant TNFRSF9 protein was found to crosslink with TNFSF9 on acute myeloid leukaemia cells. It induces reverse TNFSF9 signaling, resulted in the differentiation of primary acute myeloid leukemia cells . Recently, several studies have investigated the expression of TNFSF9 on solid tumors and found that it was indeed downregulated in various tumor cell lines, including colorectal cancer, multiple myeloma, lung cancer and breast cancer .…”

“…It induces reverse TNFSF9 signaling, resulted in the differentiation of primary acute myeloid leukemia cells. 36 Recently, several studies have investigated the expression of TNFSF9 on solid tumors and found that it was indeed downregulated in various tumor cell lines, including colorectal cancer, multiple myeloma, lung cancer and breast cancer. 11,12,37,38 In lung cancer, TNFSF9 expression was positively correlated with welldifferentiated tumors, an early TNM stage and better survival.…”