Reprogramming Lung Carcinoma Cells Into Antigen Presenting Cells

June 3, 2020
MSc. Thesis - Lund University

Ariane Tenreiro

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Cancer always plays a constant hide and seek game with the immune system. Tumor cells have developed multiple mechanisms to evade the immune system, including dendritic cells (DCs). DCs are in charge of obtaining antigens from cancer cells and present them to other cells such as Natural Killer cells and T-cells, which in turn are capable of eliciting an immune response. Unfortunately, one of the mechanisms used by cancer cells to hide from the immune system is inhibiting dendritic cells in the tumor site.

In an effort to increase DCs in the tumor microenvironment, the Pereira lab at Lund University discovered that the combination of three proteins PIB (PU.1, IRF8, and BATF3), was able to reprogram fibroblasts, a type of skin cells, into induced-dendritic cells. Further research showed that the PIB combination was capable of reprogramming cancer cells into induced tumor-antigen presenting cells (tumor-APCs) in a broad range of tumor types. Although the PIB combination showed extraordinary reprogramming efficiency in some cancer types such as melanoma and glioblastoma (up to 70%), reprogramming efficiency of other malignancies, e.g. lung carcinoma, were as low as 0.1%.

Lung carcinoma is the leading cause of cancer mortality worldwide, mainly due to the late diagnosis and lack of efficient treatment options. Therefore, increasing reprogramming efficiency of lung carcinoma would play an important role in the search for new, more effective treatment therapies. To do so, lung carcinoma and highly efficient glioblastoma cell lines were characterized at the protein, gene expression, and morphologic levels to assess the possible differences and their correlation with reprogramming efficiency. Subsequently, extrinsic factors were added to the investigated cell lines to evaluate variations in reprogramming efficiency.

Through observations of surface markers, protein levels, and gene expression changes in the cell lines, it was shown that lung carcinoma cells are capable of undergoing molecular reprogramming upon PIB treatment, however, at lower levels than the highly efficient glioblastoma cell lines. These results hinted that lung carcinoma cell lines may have a barrier that obstructs the reprogramming pathway. To further investigate this, small molecules modifying gene expression were added to the culture during the 9 days of reprogramming. The results from these experiments showcased an increase of partially reprogrammed cells from 5% to 45%, and an increase of fully reprogrammed cells from 0.1 to 12%.

Overall, increasing reprogramming efficiency of lung carcinoma cells was achieved through the addition of the small molecules. These findings contribute to a significant improvement of reprogramming efficiency that could be applied not only to lung carcinoma, but a broad range of tumour types, paving the way towards a novel immunotherapeutic approach, where the immune system would be able to win in the hide and seek game against cancer.