Cancer refers to a category of diseases where cells behave abnormally and proliferate rapidly, eventually spreading to other parts of the body. While cancer cells are one’s own cells, they become so mutated that immune cells can recognise them as almost foreign pathogens, allowing them to mount a targeted immune response against cancer cells. Moreover, cancer cells, much like pathogens, can evade immune-surveillance and dampen anti-tumour immune responses. The study and manipulation of this dynamic interaction between cancer and immune cells has laid the underpinning for a novel therapeutic approach to cancer – cancer immunotherapy. While it is important for one’s immune system to generate robust immune responses against potentially harmful stimuli, it is equally important for the immune system to resolve such an immune response, as a persistent or over-zealous response can be just as damaging. Therefore, cells of the body are equipped with molecules to help inhibit immune responses, termed “immune checkpoints”. When T cells interact with a cancer cell, they are overwhelmingly suppressed by the PD1-PDL1 interaction. Researchers have developed a monoclonal antibody therapy that binds to PDL1, blocking the interaction with PD1 on T cells and relieving the immunosuppression imparted by the tumour. The result is enhanced immune-mediated killing of the tumour. This immunotherapy has moved into clinical trials, where it has been extremely effective in PDL1-expressing tumours, particularly in forms of malignant melanoma. In fact, the 5-year survival rate of malignant melanoma patients undergoing PD1/PDL1 therapy has more than doubled. Blockade of a similar inhibitory receptor, CTLA4, has comparable potential.
While most cancer immunotherapy strategies target the adaptive branch of the immune system, immunogenic cell death (ICD) inducers aim to alert the innate branch. This strategy involves using chemotherapeutic drugs to provoke a type of cell death in tumour cells that will activate innate immune cells, which can consequently orchestrate an all-encompassing anti-tumour immune response. When cancer cells die, for example, by necrosis, they release molecules called danger-associated molecular patterns (DAMPs) that are usually contained within the cell, not in the extracellular milieu. These DAMPs can be recognised by receptors on macrophages and dendritic cells, including toll-like receptors (TLRs), and initiate a broad immune response in what is termed “sterile inflammation”. While this finding stemmed from chemotherapy research, scientists are now focusing on identifying drugs that can induce immunogenic cell death of cancer cells and instigate an immune response. Herein lies an opportunity to bridge chemotherapy with immunotherapy.