Deciphering the molecular rules that govern CD4+ T cell responses to tumour associated antigen peptides to enhance anti-tumour immunity

Harnessing the power of the immune system to fight cancer has resulted in a new era of cancer treatments. Our own body’s immune system was first thought to only fight off invading foreign bugs such as viruses and bacteria, however, it is now appreciated that the immune system is able detect cancer during an individual’s lifetime. In fact, for cancer to develop in a patient, the cancer must progress in such a way that it is able to avoid the action of watching immune system. Understanding this process has led to treatments, termed cancer immunotherapies, which aim to make the immune system better at recognising cancer so that a patient’s own body can find back stronger against the cancer. These therapies have proven incredibly powerful; however, much work is still needed to make these therapies work in everyone as well as financially viable and practically achievable to be delivered on wide scale for everyone by healthcare systems like the NHS.

An important arm of the immune response against cancer are T helper cells, named because of their development in the Thymus and their function to help and orchestrate the entire immune response  towards a target. T helper cells recognise cancer by monitoring the body for small signs of cancer occurring. These small signposts – called peptides – are scanned by T cells to determine whether or not an immune response should be enacted.

T helper cells hold the power to license and instruct the immune response towards the destruction of a cancerous cell. Whilst this is a very power function, these immune cells must be very strictly trained by our bodies on what they should target – as if the immune system is directed towards normal healthy tissues, T cells can cause disease (known as autoimmunity). For this reason, before T helper cells are released from the thymus to patrol the body, they are trained not to respond to our own body (termed “self”). This has important consequences on how well T helper cells recognise signpost peptides of cancer, as cancer peptides are also derived from “self”. It is for this reason that fewer cancer “signpost” peptides are seen by T helper cells and those that are seen are seen less well. As a result, it is important to explore ways to better train T helper cells to see and target cancer.

One of the ways to try and achieve this is to re-train the immune system to better recognise cancer through vaccination – just like vaccines protect people from viruses. There are challenges, however, to achieving this goal.  Firstly, it is important to identify the cancer peptide “signposts” that T helper cells can recognise and understand why these peptide “signposts” are seen out of the thousands of others that are not seen – this is Aim 1 & 2 of this project. Having identified which peptide signposts are seen it will be possible to explore whether these peptides can be subtly altered so that they are seen better by T helper cells – Aim 3. Finally, having identified ways to optimise the cancer signpost peptides that are seen, it will be explored whether this tactic can be applied to parts of cancer which are not normally seen – Aim 4. Together, it is hoped that increasing the magnitude of the immune response to cancer peptides and broadening the number of cancer signpost peptides the immune system can see may identify a way that cancer vaccines can be designed in the future to stimulate a better immune response against cancer.