Differential expression of granulysin and perforin by NK cells in cancer patients and correlation of impaired granulysin expression with progression of cancer

Abstract

Granulysin has been identified as an effector molecule co-localized with perforin in the cytotoxic granules of cytotoxic T lymphocytes and natural killer (NK) cells, and has been reported to kill intracellular pathogens in infected cells in the presence of perforin and to induce a cytotoxic effect against tumor cells. The aim of the present study was to elucidate whether intracellular expression of granulysin and perforin by NK cells might be associated with progression of cancer. Flow cytometric analysis demonstrated high levels of perforin and granulysin expression by CD3(-) CD16(+) cells in healthy controls. In contrast, cancer patients exhibited significantly decreased levels of granulysin expression ( P<0.005), despite having equally high levels of perforin expression in comparison with healthy controls. The tumor-free patients expressed granulysin at levels similar to healthy controls, while the progressive tumor-bearing patients expressed remarkably lower levels of granulysin compared to healthy controls ( P<0.0001). Similarly, patients with an advanced performance status had significantly fewer granulysin-positive NK cells than healthy controls. Meanwhile, a considerable number of the tumor-bearing patients showed a decrease in the number of circulating NK cells, and a correlation between impaired granulysin expression and reduced circulating NK cells was observed. These findings suggest that the tumor-bearing patients with impaired granulysin expression were in an immunosuppressive state. In conclusion, impaired expression of granulysin by NK cells correlates with progression of cancer, and determination of granulysin expression might prove informative for assessing the immunological condition of cancer patients.

In vivo rejection of tumor cells dependent on CD8 cells that kill independently of perforin and FasL

“…It has been reported that other cytotoxic molecules that are constituted in a granule, for example granulysin, 41 can be involved in the perforin-independent CTL killing. 42 Moreover, since granzyme B can directly enter target cells by a receptor, without the involvement of perforin, the cells can be induced to undergo apoptosis by both perforin-and FasL-independent pathways. 43 Another interesting observation was that, while caspase activation was only partially required to induce 39.5-B7 lysis by perforin-mediated cytotoxicity, perforin-independent CTL lysis of 39.5-B7 cells required caspase activation to transmit death signals to the cells.…”

Granulysin, a Cytolytic Molecule, Is Also a Chemoattractant and Proinflammatory Activator

“…Granulysin-mediated cytolysis occurs at 10 -100 M (1, 6, 23) while chemotaxis and immune cell activation occurs at much lower concentrations. Granulysin functions in innate immunity as it is released in the cytolytic granules of NK cells (5,24). In this study we show that granulysin released by CTL and NK cells in the local inflammatory environment has multiple biologic activities: in the immediate area, high concentrations of …”

“…Granulysin also kills human tumor cells, and expression of granulysin in peripheral NK cells from cancer patients has been associated with good clinical outcomes (5). Granulysin is a member of the saposin-like protein family of lipid binding proteins and colocalizes in cytolytic granules with perforin and granzymes (2).…”

Analysis of serum granulysin in patients with hematopoietic stem‐cell transplantation: Its usefulness as a marker of graft‐versus‐host reaction

“…Granulysin has been demonstrated to possess antimicrobial effects by itself against a variety of pathogens including bacteria, fungi, and parasites [17][18][19]. In addition, granulysin is believed to contribute to anti-tumor and antiviral immune responses through its tumoricidal and antiviral activities [20,21]. It has been also reported that mRNA of granulysin is increased in the acutely rejected kidney [22].…”