T-cell-mediated proinflammatory cell death and lysis in cancer

The primary objective of cancer treatment is to eliminate cancer cells, traditionally achieved through surgery, toxic drugs, and radiation. However, a notable approach that has gained considerable attention over the last decade is immunotherapy, where doctors and scientists aim to leverage our immune system to target and destroy cancer cells. A key player in this groundbreaking strategy is a group of assassin immune cells known as cytotoxic T lymphocytes (CTLs). These cells possess the remarkable capability of detecting cancer cells by recognising abnormal molecules on their surface that are absent in healthy cells and destroying them by releasing toxic molecules to initiate their self-destruction. While considerable efforts have been dedicated to understanding how CTLs are activated and how they recognize cancer cells, there is a gap in our knowledge about the subsequent events within cancer cells that coordinate their death. CTLs have been found to initiate two different types of cancer cell death: the first, called apoptosis, is a silent and orderly process where cells shrink and break apart into smaller pieces without alerting the immune system; the second, pyroptosis, is a more dramatic process involving the creation of openings in the cell membrane, leading to cell swelling and bursting. During this cell burst, the contents inside the cells are released into the surroundings, potentially acting as ‘danger signals’ that could stimulate a stronger immune response against the cancer. The importance of this cell burst in enhancing the anti-tumour responses will be investigated in this project. Furthermore, we are intrigued by the possibility of uncovering additional, yet unknown, forms of cell death induced by CTLs. Exploring these death-related processes within cancer cells holds potential to substantially boost the effectiveness of immunotherapy in the ongoing battle against cancer.

The primary goal of most cancer therapies is to induce cancer cell death. Immunotherapy relies on the cytotoxic activity of lymphocytes such as natural killer cells (NKs) and cytotoxic T lymphocytes (CTLs) to achieve this. While a significant amount of research in immunotherapy focuses on the events within cytotoxic lymphocytes or at the interface between cytotoxic lymphocytes and cancer cells, less is known about the molecular mechanisms that orchestrate cancer cell death, particularly in the case of CTL-mediated death. CTLs are known to induce two types of cell death in cancer: non-inflammatory apoptosis and proinflammatory pyroptosis. Pyroptotic cancer cells release proinflammatory signals that attract immune cells to the tumor site, thereby enhancing the anti-tumor response. Cell lysis is a common outcome of pyroptotic cell death. It is unclear whether lysis can be decoupled from pyroptosis in cancer cells and whether the proinflammatory properties of pyroptotic cancer cell death depend on lysis. Moreover, it remains unknown whether CTLs can induce other forms of cell death in cancer, apart from apoptosis and pyroptosis. Studying the mechanisms of CTL-mediated cancer cell death is challenging because CTLs selectively target cells expressing specific antigens. However, given the critical role of CTLs in immunotherapy, it is essential to deepen our understanding of CTL-induced cancer cell death. This project aims to develop novel methodologies to investigate the death mechanisms that are initiated by CTLs. In addition, we will identify new pathways and mediators involved in CTL-induced cancer cell death. Furthermore, we will assess the contribution of proinflammatory cell death and lysis in promoting anti-tumor responses in vivo. Overall, this research will improve our knowledge of the molecular mechanisms of CTL-mediated cancer cell death and potentially reveal novel targets to enhance the efficacy of cancer immunotherapy.