The Role of Physical Membrane Properties in Tumour Cell Resistance to Perforin

To kill virus-infected and cancer cells, the human immune system can use white blood cells that expose their targets to a mixture of toxic proteins. This is exploited by so-called cancer immunotherapies, which induce the immune system to more effectively target tumours. However, the success of these therapies strongly depends on the type of cancer and can be remarkably variable - even for the same type of cancer - from one patient to the other, for reasons that remain poorly understood.

In the mix of proteins secreted by these white blood cells, an essential protein is perforin, which punches holes in the target cells. We have only recently discovered how the white blood cells are protected against the perforin they secrete, preventing them from being damaged every time they kill a target (e.g., a cancer cell). This protection resides in the physical properties of the membrane that surrounds the white blood cells, in particular in how the fatty acid molecules ("lipids") in the membrane are packed and what electric charge they have at the membrane surface.

With this project, we aim to investigate if a similar protection may be used by cancer cells, to protect them against perforin and to thus reduce the efficiency at which they are cleared by the immune system. If this is the case, this can be used as an inspiration for strategies that enhance the efficacy of cancer immunotherapies and/or as a way to test patient resistance to such therapies before they are treated.

Immunotherapies represent this century's most revolutionary progress in the treatment of cancers. However, in spite of some spectacular success, many patients show incomplete or poor response to treatment, and in many instances, tumours become resistant to immune killing for reasons that are still poorly understood. For the critical effector phase, all these therapies rely on cytotoxic T lymphocytes and, occasionally, natural killer cells, and their killing of target cells mediated by an essential pore forming protein called perforin. We have recently discovered that cytotoxic T lymphocytes are protected against their own perforin by lipid order and charge in their plasma membranes, thus allowing them to kill multiple targets in succession without succumbing to self-harm. Based on that observation, we have hypothesised that cancer cells may use similar lipid-based, physical mechanisms to evade immune killing by resistance to perforin. If so, we anticipate that such mechanisms also play a role in defining tumour cell resistance - and ultimately patient response - to cancer immunotherapies, including CAR T-cell therapy. With this project, we aim to test that hypothesis, based on a combination of biophysical and immunobiological expertise, in addition to access to well annotated patient samples.