Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Sarsembayeva, A.
Regulation of tumor growth and immune cell microenvironment by cannabinoid receptor 2 in non-small cell lung cancer
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2023. pp. 105
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Böhm Eva
- Kargl Julia
- Schicho Rudolf
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- Abstract:
- Lung cancer is the most frequently diagnosed type of cancer, and it remains a leading cause of cancer-associated deaths worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 85% of all lung cancer cases. Cannabinoid receptors 1 and 2 (CB1 and CB2) are part of the endocannabinoid system that are expressed in tumor cells of various cancer entities, including lung cancer, and they are well-known to influence tumor growth. Additionally, cells of the tumor surrounding niche, called tumor microenvironment (TME) also express CB1 and CB2, however, their role in tumor development has not been elucidated yet. As a consequence, we investigated the influence of TME-derived CB1 and CB2 on tumor growth in a model of NSCLC. To create a TME deficient in CB receptors, we used a murine NSCLC model in which CB1- (CB1-/-) and CB2-knockout (CB2-/-) mice or their wild type (WT) littermates subcutaneously received KP (Kras mutant, Trp53-null) lung adenocarcinoma cells. In situ hybridization and immunofluorescence were performed to determine expression of CB1 and CB2 transcripts in tumor and immune cells. Using flow cytometry, the profile of immune cells of the TME was analyzed. Tumor cells and tumor-infiltrated immune cells of murine and human NSCLC both express CB receptors. The expression of CB2 mRNA in tumor-infiltrated immune cells was higher than of CB1. We observed that gene knockout or pharmacological blockade of CB2, but not of CB1 resulted in a significant reduction of tumor growth. Deletion of Cnr2 (the gene encoding CB2) on host cells induced increased infiltration and local anti-tumorigenic activity of CD8+ T and natural killer (NK) cells. Moreover, it increased the expression of C-C motif chemokine ligand 21 (CCL21), and the expression of programmed death-1 (PD-1) and its ligand (PD-L1) on lymphoid and myeloid cells, respectively. In addition, expression of CCR7 (CCL21 receptor) was significantly reduced on CD8+ T and NK cells from CB2-/- vs. WT mice. Importantly, mice lacking the Cnr2 gene responded significantly better to anti-PD-1 blocking therapy than WT mice. The immunotherapy with anti-PD-1 antibodies further increased infiltration of CD8+ T and NK cells into the TME of CB2-/- mice. Altogether, the findings presented in this thesis suggest that TME-derived CB2 plays a pro-tumorigenic and immunosuppressive role in murine NSCLC tumors by limiting cytotoxic activity of CD8+ T and NK cells. Knockout of CB2 in TME cells of NSCLC could provide additional clinical benefit to anti-PD-1/PD-L1 therapy.