Die Rolle von "Innate Lymphoid Cells" im humanen Kolorektal-Karzinom.
Zusammenfassung der Projektergebnisse
Colorectal cancer is among the leading causes of cancer-related deaths in Europe. As infiltration of immune cells into the tumour is associated with better prognosis, understanding the immunological processes therein is key to developing new interventions. Innate lymphoid cells (ILCs) are one of the central players in the regulation of intestinal homeostasis. In this project, we addressed the role of ILCs in the pathogenesis of human colorectal cancer. Firstly, we observed that ILCs in colorectal tumours differ in surface and functional characteristics compared to their counterparts in healthy tissue, implying an existing crosstalk between ILCs and the tumour microenvironment in colorectal cancer. Moreover, ILCs in the tumour displayed an increased expression of HLA-DR, a molecule necessary for antigen presentation to and activation of helper T cells. This suggested that ILCs might present cancer antigens to T cells and thus, regulate cellular immune responses in the tumour. Using ILCs isolated from peripheral blood we were able to demonstrate the effect of cytokines associated with colorectal cancer on the antigenpresenting properties of these cells. Pro-inflammatory cytokines interleukin (IL)-1β and IL-18 upregulated HLA-DR and induced the expression of molecules that enhance T-cell activation. Moreover, we were able to show that ILCs activated this way are able to present foreign protein antigens to memory helper T cells while inducing efficient cytokine production by the latter. On the other hand, transforming growth factor (TGF)-β, a cytokine with immunosuppressive properties, efficiently counteracted the effects of IL-1β and IL-18, abrogating the antigenpresenting characteristics of ILCs. A better understanding of crosstalk between ILCs and T cells, as well as the influence of the immediate tissue microenvironment may be instrumental for designing future immune-based therapies. This applies not only to cancer but also other intestinal diseases where inflammation might unleash the antigen-presenting capacity of ILCs and regulation of T-cell responses.
Projektbezogene Publikationen (Auswahl)
- “Lung inflammation originating in the gut”. Science. 2018 Jan 5;359(6371):36-37
Mjösberg J, Rao A
(Siehe online unter https://doi.org/10.1126/science.aar4301) - “The roles for innate lymphoid cells in the human immune system”. Semin Immunopathol. 2018 Jul;40(4):407-419
Mazzurana L, Rao A, Van Acker A, Mjösberg J
(Siehe online unter https://doi.org/10.1007/s00281-018-0688-7) - “Innate lymphoid cell type 3-derived interleukin-22 boosts lipocalin-2 production in intestinal epithelial cells via synergy between STAT3 and NF-κB”. J Biol Chem. 2019 Apr 12;294(15):6027-6041
Coorens M, Rao A, Gräfe SK, Unelius D, Lindforss U, Agerberth B, Mjösberg J, Bergman P
(Siehe online unter https://doi.org/10.1074/jbc.RA118.007290)
