Constitutive Expression of Functional 4-1BB (CD137) Ligand on Carcinoma Cells

Abstract

Members of the TNF superfamily, including Fas, Fas ligand, and CD40, have been shown to be expressed on tumor cells. In the studies described in this work, we report that another family member, the ligand for 4-1BB (CD137), is expressed on various human carcinoma cell lines, on cells of solid tumors derived from these cell lines, and cells obtained from human tumors. Expression of 4-1BB ligand (4-1BBL) mRNA was detected by both RT-PCR and Northern blot analysis, and expression of 4-1BBL protein was detected by Western blot analysis of whole cell lysates and by FACS analysis of tumor cells and cell lines. Incubation of tumor cells with a 4-1BB-Ig fusion protein led to the production of IL-8 by the cells, demonstrating that the 4-1BBL is functionally active and signals back into the tumor cells. Furthermore, 4-1BBL expressed on the carcinoma cells functioned as a costimulatory molecule for the production of cytokines (most notably IFN-γ) in cocultures of T cells and tumor cells. These findings suggest that 4-1BBL expressed on carcinoma cells may significantly influence the outcome of a T cell-tumor cell interaction.

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

“…Functional expression of 4-1BBL has been described on various healthy cell types including B cells, but also on malignant cells of various origins [16,[20][21][22]. We here analyzed 4-1BBL expression on primary human B-CLL Cells (CD5 1 CD19 1 ) from a total of 56 patients.…”

“…As 4-1BBL signaling can induce release of TNF and IL-8 by malignant cells [16,21] and because the levels of these cytokines correlate with prognosis of CLL patients [23,24] we determined whether the CLL-expressed 4-1BBL was capable to transduce signals resulting in the production of immunomodulatory cytokines. Primary CLL cells of patients were cultured alone or on immobilized 4-1BB-Ig (which enables multimerization of 4-1BBL) with IgG1 serving as the isotype control.…”

Role of 4-1BB:4-1BB ligand in cancer immunotherapy

“…13 4-1BBL was also present at high levels in the sera of some patients with hematological diseases 35 as well as on some carcinoma cell lines. 36 The inducible expression pattern of 4-1BBL was similar to that of B7-1 and B7-2 in the CD28:B7 pathway. The costimulatory molecules B7-1 and B7-2 were expressed at very low levels in resting APCs and upregulated upon activation by surface Ig.…”

4-1BB (CD137) Ligand Enhanced Anti-Tumor Immune Response against Mouse Forestomach Carcinoma In Vivo

“…One signal occurs through the TCR:MHC:Ag complex while the other is provided through co-stimulation. T cell will be anergic in response to one signal alone if co-stimulation is absent (2,3,5). A number of studies have demonstrated effective anti-tumor targeting in clinical trials using the co-stimulatory molecules but to date these have almost utilized the B7:CD28 pathway (17).…”

“…These T cells then receive a second set of signals on binding of their co-stimulatory molecules to the corresponding molecular pairs on the APCs, and the T cells become activated. Without co-stimulation, T cells will undergo apoptosis or become anergic (2)(3)(4)(5)(6). The fact that tumor cells are found to have low co-stimulatory molecule expression may explain how tumor cells evade the immune system.…”