Cancer cells co-opt several physiologic regulatory mechanisms to resist immune attack. It has been suggested that one such cancer-corrupted immunologic checkpoint may be tumor cell expression of Fas ligand (FasL) to “counterattack” Fas-sensitive infiltrating T (and natural killer) effector cells. The Fas pathway functions physiologically to limit the size of antigen-stimulated immune cell clones via a process termed activation-induced cell death. In addition, physiological cellular expression of FasL may protect immune privileged organs, such as eye, brain, testis, and placenta, from immune damage by inducing apoptosis of invading Fas-sensitive inflammatory cells (1).
Several types of human cancers express FasL and mediate apoptosis of Fas-sensitive T cells in vitro (2–4). Tumor cell FasL expression has been associated with decreased numbers of tumor-infiltrating lymphocytes and increased numbers of apoptotic lymphocytes in human colon and esophageal carcinomas (5, 6). Cancer cell FasL expression has also been correlated with (a) the ability of tumor cells to inactivate neutrophils, (b) tumor growth rate, and (c) patients' prognosis (7–12). Moreover, FasL expression levels were found to be higher in liver metastases of human colorectal carcinoma than in matched primary tumors (13). Based on such findings, it has been suggested that FasL-expressing tumor cells locally counterattack tumor-infiltrating lymphocytes, thereby establishing immune privilege for the cancer mass.
This FasL counterattack hypothesis has been challenged by studies showing that artificially enforced overexpression of FasL in tumors enhanced tumor rejection rather than tumor survival (14, 15). Adding to the controversy are key technical issues, such as the specificity of the anti-FasL antibodies used, and the need to distinguish FasL counterattack by tumor cells from apoptosis due to physiological activation-induced cell death (16–19). In addition, whereas metalloprotease-mediated release of FasL from tumors has been proposed as a mechanism of counterattack, it has been found that the resulting soluble form of FasL functions more as a competitive inhibitor of cell membrane FasL than as a (weak) agonist. Finally, tumor cell expression of other proteins, such as transforming growth factor-β (20, 21), may be equal or more important factors in tumor immune resistance. Perhaps a reasonable synthesis is to predict that further investigations will demonstrate that expression of FasL is only one of a complex set of mechanisms by which certain cancers may inhibit immune attack.
In this issue of Clinical Cancer Research, Kim et al. investigated a nuanced version of this FasL counterattack mechanism to explain the apoptosis of circulating T lymphocytes and the associated decreased T cell receptor-associated signaling molecule ζ-chain expression that they had previously documented in patients with oral squamous cell carcinoma (22). This research group also observed apoptosis of circulating T lymphocytes and decreased expression of T cell receptor-ζ-chain in patients with squamous cell carcinoma of the head and neck and malignant melanoma (23–25), and they suggested that these tumors have immunosuppressive effects on circulating lymphocytes, as well as on tumor-infiltrating lymphocytes. Andreola et al. (26) showed that melanoma cells generated FasL-containing membrane microvesicles (FasL-MVs) that mediated apoptosis of T lymphoid cells, and Taylor et al. (27) found similarly immunosuppressive FasL-MVs in the sera of patients with ovarian cancer. Kim et al. now report that FasL-MVs isolated from sera of patients with oral squamous cell carcinoma, but not from normal controls, induced apoptosis of FasL-sensitive T lymphoid target cells and down-regulated expression of the T cell receptor-ζ-chain. Both apoptosis and ζ-chain down-regulation were partially inhibited by either an anti-Fas neutralizing monoclonal antibody or a peptide caspase inhibitor. Levels of FasL-MVs in the serum of patients with oral squamous cell carcinoma correlated positively with levels of apoptosis induction and negatively with ζ-chain expression. These results, along with the similar observations in ovarian cancer (27), suggest that FasL-MVs (possibly along with the other proapoptotic molecules) from tumor cells can impair not only lymphocytes in the local tumor microenvironment (i.e., tumor-infiltrating lymphocytes), but also distant lymphocytes (Fig. 1). It is important to note that these FasL-MVs were shown to contain the membranous full-length form of FasL, rather than the less potent (and even inhibitory, see above) metalloprotease-cleaved soluble FasL molecule. Furthermore, this report includes preliminary results in a small series of patients indicating that the level of FasL-MVs might serve as a prognostic factor in oral squamous cell carcinoma.
FasL-MV-mediated tumor counterattack. Tumor cells attack tumor-specific circulating T cells by releasing microvesicles containing FasL-MVs into the blood. Note that because the tumor cells also express FasL on their cell membranes, they can also directly attack T cells that infiltrate the tumor site.
FasL-MV-mediated tumor counterattack. Tumor cells attack tumor-specific circulating T cells by releasing microvesicles containing FasL-MVs into the blood. Note that because the tumor cells also express FasL on their cell membranes, they can also directly attack T cells that infiltrate the tumor site.
What are the next steps? As noted by Kim et al., the source of the shed FasL-MVs has not yet been proven to be the cancers. Further studies are needed to test the possibility that FasL-MVs are merely the product of activation-induced cell death of normal activated lymphocytes. It will also need to be determined if FasL-MVs are found in sick control patients without cancer, especially patients with immune disorders. Of course, large prospective studies are needed to test the prognostic utility of serum levels of FasL-MVs. However, FasL-MVs may prove more important as part of the complex profile of the conflagration between the cancer and the immune system than simply as a clinical prognostic factor.
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