MICA: Investigating the role of the adenosinergic pathway in anti-tumour immune dysfunction in cutaneous squamous cell carcinoma (cSCC)

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Cutaneous squamous cell carcinoma (cSCC) is one of the commonest cancers worldwide, with >44,000 diagnosed in the UK annually. Most cSCCs are treated with surgery, but when the cancer is advanced or has spread to other organs (called metastasis) treatment options are limited. Cancers are surrounded by immune cells which play a crucial role in killing the cancer, but these cells are frequently "paralysed" by the cancer, allowing the tumour to progress. Cancer immunotherapies encourage the immune cells to attack cancers, and are revolutionising the treatment of advanced/metastatic cancer. In cSCC, an immunotherapy targeting the PD-1 pathway (Cemiplimab) has been shown to improve survival, but only gives a complete response in around 15% of patients. Therefore, we urgently need to identify new immunotherapy targets to help enhance anti-cancer immune responses in cSCC. Adenosine is a chemical produced in cSCC that can cause immune suppression in cancer. I predict that using treatments designed to block the adenosine pathway will stop adenosine inhibiting the immune cells and boost the immune response in cSCC, leading to a potential new treatment for this cancer. Additionally, I predict that by combining adenosine blockade with anti-PD-1 treatment, it may be possible to enhance the effect of anti-PD1 treatment. Objective 1: How do treatments blocking the adenosine pathway in cSCC affect anti-cancer immune cell responses? Using a novel 'tissue slice culture' (TSC) system, I will culture very thin slices of freshly removed, live cSCC with three different adenosine pathway blockers (CD39 inhibitor, anti-CD73 antibody, and an A2AR inhibitor), that block the production or action of adenosine at different positions in the pathway. The effects of these different treatments on cSCC immune cells will be assessed by looking at protein changes, tumour killing and gene-expression levels, the latter using a state-of-the-art approach called single cell transcriptomics. This is a technique that shows which genes are active in each individual cell within the sample, so it tells us how individual cells and groups of immune cells respond. The TSC system has the advantage of investigating the immune cells' behaviour within the tumour environment, while allowing me to focus on how individual subsets of immune cells respond to the different adenosine pathway blockers to determine their individual effects in cSCC.Objective 2: Does combining adenosine pathway blockers boost the anti-cancer immune response in cSCC more than blocking the adenosine pathway using individual agents? I will treat cSCC slices (using the TSC system) with all the adenosine blockers together (CD39 inhibitor, anti-CD73 antibody, and an A2AR inhibitor) and compare it with using the treatments separately (as above). I will see how this changes the immune cell activity by looking at the gene expression of key genes, whether the immune cells make certain proteins that are known to increase their anti-cancer effects, and whether the combination of adenosine pathway blockers kills more cancer cells.Objective 3: Does combining adenosine blockade with anti-PD-1 improve the anti-cancer immune response over that seen with anti-PD-1 alone?I will combine adenosine pathway blockers with an anti-PD-1 immunotherapy to see if this combination gives a bigger boost to the immune cells than using either approach alone. I will assess the immune responses and cancer cell killing in the same way as outlined in Objective 2.Future Benefits: The results will enhance our understanding of how the adenosine pathway acts in cSCC and whether combining blockade of this pathway with existing anti-PD-1 immunotherapy may be useful. This will inform the direction of future clinical trials with these agents. In addition, the techniques developed in this project may be useful for future research assessing different immunotherapy combinations for other types of cancers.