Cancer Cell Death

Cancer Cell Death - Research at Peter Mac

We investigate immune mechanisms of defence against viral pathogens and cancerous (transformed) cells. Understanding these processes will help to (1) better understand molecular mechanisms that govern the immune system; (2) design and rationally apply anti-cancer therapy alone or in combination with immunotherapy; (3) identify genetic predisposition to haematological malignancies; (4) design novel therapeutic approaches to prevent life-threatening complications of tissue transplantation.

Overview

The immune system is a complex and essential barrier that protects organisms against pathogens. It is now also recognised as the major defence mechanism against pre-cancerous and even metastatic cancerous cells. However, the mechanisms that govern the destruction of these cells by cytotoxic lymphocytes (CL) are yet to be fully understood. The Cancer Cell Death Laboratory has a long-standing interest in elucidating the mechanisms and regulation of CL activity with the major focus of our studies being key cytotoxic molecules: pro-apoptotic proteases, granzymes, and a pore-forming protein, perforin (PRF). Transient contact between a CL and a target cell leads to the secretion of granzymes and PRF, which synergistically induce rapid apoptotic death of the unwanted cell. This process of target cell recognition and destruction by CLs is called immune surveillance; its breakdown leads to a greater predisposition to cancer and increased susceptibility to viral infections.

By dissecting the role of individual components of CLs, we have shown the mechanisms underlying apoptotic activity of granzymes, particularly their role in the mitochondrial death pathway. As this may be counteracted by the anti-apoptotic molecule Bcl-2, which is overexpressed in many cancers, we are now developing strategies aimed at neutralising its activity and thus making a cancer cell more sensitive to immune surveillance.

Pore-forming PRF is absolutely essential for immune surveillance of cancer and viral infections in experimental animals and, more recently, its role in maintaining immune homeostasis and protection against viral infections has been demonstrated in humans. Despite this progress in the field, the mechanism of PRF’s action and its role in human cancer remained unknown. Our laboratory has led the world in understanding the molecular mechanisms of PRF pore-formation and its role in disease. We have developed experimental strategies that have allowed us insight into PRF’s mechanism of pore formation and synergy with granzymes. We have also demonstrated that partial PRF deficiency predisposes individuals to haematological malignancies or atypical infections. Our studies have revealed previously unappreciated genetic regulation of PRF expression, and we are currently investigating its role in pathologies.

In certain pathologies, PRF-dependent CL activity leads to life-threatening tissue damage, which is particularly evident in (i) xenograft rejection, (ii) autoimmunity such as type I diabetes, where pancreatic beta cells are targeted and killed by CLs, and (iii) during the course of a frequently fatal complication of bone marrow transplantation resulting in graft-versus-host disease, where cells in the gut and skin are attacked by the immune system. One of the directions of our research is, therefore, the development of novel therapeutic strategies to alleviate undesired effects of CL activation through targeted inhibition of PRF activity.

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