Granzyme M, a profiler of innate immune lymphocytes?

There is currently a major effort underway to identify the protein expression patterns (proteome) of various tumor cells. Indeed, characteristic patterns of protein expression may help determine the specific cellular origin of the malignant cell. In this issue, Krenacs and colleagues (page 3590) studied granzyme M (GM) expression in various lymphomas. The granzymes (or granule enzymes) are a family of related serine proteases that have a restricted expression within cells of the lymphoid system. These enzymes are expressed in natural killer (NK) cells and in T cells (predominantly CD8⁺“cytotoxic” T cells) following activation (Smyth et al, J Leuk Biol. 2001;70:18-29). The granzymes are absent from macrophages, neutrophils, and B cells.

The expression of GM seems even more restricted than other granzymes. GM is present in normal blood in rare lymphocytes such as NK cells, γ/δ T cells, and CD3⁺ CD56⁺ T cells, yet is absent from T cells of the adaptive immune system even following activation (Sayers et al, J Immunol. 2001;166:765-771). Krenacs et al found expression of GM in 100% of NK/T lymphomas and γ/δ T-cell lymphomas and in 85% of intestinal T-cell lymphomas. Intestinal αβ CD8⁺ intraepithelial lymphocytes also expressed GM, leading to the provocative suggestion that these cells may really be components of the innate immune system (despite their rearrangement of the αβ T-cell receptor).

GM expression was therefore maintained after tumorigenesis, and in some situations this could have practical utility. The authors noted that discrimination between some intestinal T-cell lymphomas (ITCLs) and systemic anaplastic large cell lymphomas (S-ALCLs) is sometimes difficult, yet in contrast to ITCLs, S-ALCLs rarely express GM. This distinction would have clinical implications, since ITCL has a much poorer prognosis than S-ALCL. Therefore, as demonstrated in this study, GM does seem to be a useful additional marker for a further subclassification of lymphomas. But the biologic function(s) that this unusual enzyme performs during an innate immune response remains mysterious and worthy of further investigation.