Potential immunoregulatory role of T and dendritic cells in cancer : Investigations based on transcriptional analysis

Sammanfattning: AbstractCancer is a complex disease with various genetic and epigenetic driving factors. Cancer cells form a favored microenvironment to sustain their uncontrolled behavior leading to abnormal growth. With standard treatment including chemotherapy, relapse risk is high due to the resistance that cancer cells can develop against chemotherapy agents. Immuno-oncological therapeutics, as alternatives, have shown very promising clinical results in treatment of patients with different malignancies. Although promising, such treatments are facing many significant challenges, resulting in clinical benefits for only a small group of patients. T cells and dendritic cells, as two of the critical players of the immune response, are currently under investigation for development of novel immunotherapeutic approaches where boosting dendritic cells’ antigen presentation ability and restoring the effector function of T cells are the ultimate goals. In this thesis, a transcritpoic approach was used to gain knowledge on T and dendritic cell subsets in head and neck cancer, acute myeloid leukemia, and bladder cancer. In this regard, paper I and II identify different subsets of dendritic cells in tonsillar and nasopharyngeal cancer where intratumor dendritic cell subsets in tonsillar cancer are found to feature expression of inhibitory receptors and cytokines such as PDL1, PDL2, LAG3, and IL-10. Additionally, paper I introduces an array of functionally-relevant molecules on the surface of different dendritic cell subsets in tonsillar cancer, which may be useful for dendritic cell-targeted therapy given the differences in the function of dendritic cell subsets. Furthermore, selective expression of CD207 in tonsillar and nasopharyngeal cancer is shown as a proof of concept, suggesting the possibility of selective targeting of dendritic cell subsets.With respect to T cells, paper III and IV demonstrate that these are transcriptionally different in acute myeloid leukemia patients with TP53 mutation, as compared to healthy controls. Similar observation was made for T cells in bladder tumors as compared to control tissue, where cellular exhaustion was suggested. For instance, higher expression of exhaustion markers TIM3, TIGIT, CLTA4, and LAG3 was shown for CD8+ T cells in muscle invasive bladder tumors compared to non-muscle invasive tumors and control tissue. Likewise, paper III highlights some features of exhaustion in TP53-mutated acute myeloid leukemia as higher expression of TIM3 by CD8+ T cells was shown compared to corresponding control population. Potentially, the exhaustion markers shown in paper III and IV can be valuable for restoring effector function of exhausted CD8+ T cells in TP53-mutated acute myeloid leukemia and bladder cancer. In conclusion, the results presented provide insights on the immuno-regulatory role of subpopulations of T and Dendritic cells in cancer and can contribute to improved cancer therapy.