CD137 Ligand Activities on Nonhematopoietic Cells

CD137 ligand expression could be detected on human carcinoma cell lines of colon, lung, breast, ovarian, and prostate origin (Table 3.2). Crosslinking of CD137 ligand induces release of IL-8 from tumor cells (Salih et al., 2000). It is

Tumor cell

Tumor cell

CD137 ligand CC°0^CD137

Figure 3.4. Activities of the CD137 receptor/ligand system in tumor-immune interactions. Ectopic expression of CD137 ligand on tumor cells inhibits an anti-tumor immune response by inducing inhibitory signal through CD137 in T cells (A). The tumor cell would here imitate an APC in a situation in which it downregulates T cell activity via the CD137 receptor/ligand system (B). The interaction of an APC with a T cell can also enhance an anti-tumor T cell response in a physiological context which favors transmission of costimulatory signals to T cells (B).

CD137 ligand CC°0^CD137

Figure 3.4. Activities of the CD137 receptor/ligand system in tumor-immune interactions. Ectopic expression of CD137 ligand on tumor cells inhibits an anti-tumor immune response by inducing inhibitory signal through CD137 in T cells (A). The tumor cell would here imitate an APC in a situation in which it downregulates T cell activity via the CD137 receptor/ligand system (B). The interaction of an APC with a T cell can also enhance an anti-tumor T cell response in a physiological context which favors transmission of costimulatory signals to T cells (B).

at present not known whether CD137 ligand is also present on the corresponding healthy tissues or whether the tumor cells acquire CD137 ligand expression during the transformation process. It used to be puzzling why tumor cells would express CD137 ligand, which has been shown to induce an anti-tumor immune response upon transgenic expression on tumor cells (Guinn etal., 1999; Melero etal., 1998). Further, IL-8 which is a proinflammatory chemokine and is induced by reverse signaling through CD137 ligand in the tumor cells is also expected to enhance an anti-tumor immune response. However, recently it has become evident that CD137 not only costimulates T cells, but under certain circumstances can inhibit T cell activity and immune responses (Al-Shamkhani, 2004; Foell et al., 2003; 2004). It is at present not clear under which circumstances the CD137 signal is activating or inhibitory for T cells. But it is conceivable that the local environment in the tumor favors the inhibitory over the costimulatory activity of CD137 on T cells. The anti-tumor activity of infiltrating T cells would then be inhibited by tumor-expressed CD137 ligand. Thus, expression of CD137 ligand—possibly as a neoantigen—may contribute to escape of tumor cells from immunosurveillance (Figure 3.4A).

In that case the CD137 ligand-expressing tumor cell would imitate an APC in a situation where it delivers inhibitory CD137 signals to T cells (Figure 3.4B). It needs to be emphasized that the same interaction can enhance T cell activity and anti-tumor immunity in a different physiological context. Signaling through CD137 ligand into the tumor cell would not be required for this explanation of ectopic CD137 ligand expression on tumors.

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