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Improvements of immune responses against colorectal cancers and enterotoxins

Research group

Active research

Project owner

Institute of Biomedicine

Area

Health and medicine

Topic

Cell and molecular biology

Short description

Epithelial cells (ECs) of the gut are subjected to mechanical stress and can also be exposed to toxins produced by bacteria that can bind to ECs and cause lethal diarrheal diseases, such as cholera. ECs are constantly replaced by cells generated from intestinal stem cells and together with the underlying immune cells (ICs) protect the intestine from these insults. However, the high rate of stem cell division can lead to establishment of colorectal cancers. Ulf Yrlid's group uses primary intestinal ICs and enteroids (EC cultures) with two main aims: 1) Characterize novel toxin receptors on ECs and ICs to create novel antidotes and vaccines against diarrheal diseases and 2) Determine how ICs that have infiltrated colorectal cancers and metastases can be used prognostically to determine which immunotherapy and/or irradiation regime to use.

The epithelial cells lining the intestine are constantly exposed to microbes and subjected to mechanical stress. Therefore, epithelial cells need to be constantly renewed, which increases the risk of accumulation of mutations and subsequent tumor formation. Immune cells persistently survey the intestine to ensure intestinal homeostasis by initiating appropriate immune responses.

Dendritic cells are vital for generation of T cells that counteract tumors and microbial pathogens. We have previously shown that subsets of lymph borne dendritic cells have distinct roles in activating T cells in rodent models. We are now applying multicolor histology and flow cytometry for analysis of dendritic cells and T cells in human primary colorectal cancer tissues and liver metastases. We also evaluate the anti-tumor capacity of tumor infiltrating T cells in vitro and with a patient-derived xenograft model in mice.

Moreover, T cells activated in secondary lymphoid organs have to make the crucial decision on whether to stay and aid B cells, or re-enter circulation and home to the intestine. With murine transgenic models, we are determining the cellular interactions that regulate these processes, which are critical for intestinal anti-tumor responses and also following oral vaccination.

Cholera toxin greatly enhances oral immune responses but also intoxicates intestinal epithelial cells to cause the symptoms of Cholera disease. We have recently demonstrated that Cholera toxin can use a novel set of receptors. This finding could help uncoupling the toxicity of Cholera toxin from the immune activating potential and thereby aid the development of novel antidotes plus strong, yet safe, oral vaccines. In collaboration with Dr. Jen Kohler, UTS Southwestern, Dallas and Prof. Nicole Sampson, Stony Brook, New York, USA, we are now using murine models and primary human epithelial cells to determine the functional role of novel (non-GM1 related) receptors for Cholera toxin.