The mortality rate is high for cancer patients and treatments are only efficient in a fraction of patients. To be able to cure more patients, new treatments need to be invented. Immunotherapy activates the immune system to fight against cancer and one treatment targets immune checkpoints. If more targets are found, more patients can be treated successfully. In this project, interactions between immune and cancer cells that drive tumour growth were investigated in an attempt to find new potential targets. This was achieved by creating a machine learning model that finds genes expressed in cells involved in tumour-driving interactions. Single-cell RNA sequencing and spatial transcriptomic data from breast cancer patients were utilised as well as single-cell RNA sequencing data from healthy patients. The tumour rate was based on the cumulative expression of G2/M genes. The G2/M related genes were excluded from the analysis since these were assumed to be cell cycle genes. The machine learning model was based on a supervised variational autoencoder architecture. By using this kind of architecture, it was possible to compress the input into a low dimensional space of genes, called a latent space, which was able to explain the tumour rate. Optuna hyperparameter optimizer framework was utilised to find the best combination of hyperparameters for the model. The model had a R2 score of 0.93, which indicated that the latent space was able to explain the growth rate 93% accurately. The latent space consisted of 20 variables. To find out which genes that were in this latent space, the correlation between each latent variable and each gene was calculated. The genes that were positively correlated or negatively correlated were assumed to be in the latent space and therefore involved in explaining tumour growth. Furthermore, the correlation between each latent variable and the growth rate was calculated. The up- and downregulated genes in each latent variable were kept and used for finding out the pathways for the different latent variables. Five of these latent variables were involved in immune responses and therefore these were further investigated. The genes in these five latent variables were mapped to cell types. One of these latent variables had upregulated immune response for positively correlated growth, indicating that immune cells were involved in promoting cancer progression. Another latent variable had downregulated immune response for negatively correlated growth. This indicated that if these genes would be upregulated instead, the tumour would be thriving. The genes found in these latent variables were analysed further. CD80, CSF1, CSF1R, IL26, IL7, IL34 and the protein NF-kappa-B were interesting finds and are known immune-modulators. These could possibly be used as markers for pro-tumour immunity. Furthermore, CSF1, CSF1R, IL26, IL34 and the protein NF-kappa-B could potentially be targeted in immunotherapy.
| Identifer | oai:union.ndltd.org:UPSALLA1/oai:DiVA.org:uu-505563 |
| Date | January 2023 |
| Creators | Stigenberg, Mathilda |
| Publisher | Uppsala universitet, Neuroonkologi och neurodegeneration |
| Source Sets | DiVA Archive at Upsalla University |
| Language | English |
| Detected Language | English |
| Type | Student thesis, info:eu-repo/semantics/bachelorThesis, text |
| Format | application/pdf |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | UPTEC X ; 23017 |
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