Date of Award
9-27-2023
Publication Type
Thesis
Degree Name
M.Sc.
Department
Biological Sciences
Supervisor
Mir Munir Rahim
Rights
info:eu-repo/semantics/openAccess
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Abstract
Natural killer (NK) cells of the innate immune system play important roles in anti-cancer immunity. NK cell functions are regulated by inhibitory and activating receptors, which recognize specific ligands on the target cells. One example is the inhibitory NKR-P1B receptor which recognizes the ligand C-type lectin-related protein b (Clr-b). Work in our lab has shown NKR-P1B:Clr-b interactions are involved in mammary tumor immunosurveillance by NK cells. However, the cellular interactions and factors involved in modulating NK cell functions via this receptor:ligand system in the tumor microenvironment (TME) are not fully understood. This project aims to understand the role of myeloid-derived suppressor cells (MDSC) in regulating NK cell responses via the NKR-P1B:Clr-b axis in TME. Using MMTV-PyVT transgenic mouse model and E0771 mammary adenocarcinoma cells injected into wild-type (WT), NKR-P1B- deficient, and Clr-b-deficient mice to induce mammary tumors, we assessed MDSC recruitment and function in mammary tumors, and their effects on anti-cancer immune responses by NK cells. We have found that MDSCs express Clr-b, suggesting that they could potentially interact with NK cells via the inhibitory NKR-P1B receptor. However, MDSC differentiation, recruitment to tumors, and subset distribution in tumors is not affected by NKR-P1B:Clr-b axis. Our data demonstrates heterogeneity in MDSC recruitment and distribution, and inflammatory cytokine levels in MMTV-PyVT and E0771 mammary tumor models that could differentially impact NK cell responses in tumors. In in vitro co-culture assays, MDSCs induced downregulation of transcription factor EOMES, downregulation of integrins CD49a and CD49b, and upregulation of checkpoint receptor Lag-3 in NK cells, suggesting that MDSCs may induce NK cell dysfunction. Our data also show that Clr-b may have an inhibitory function in MDSCs but this is independent of NKR-P1B receptor. These findings will advance our understanding of the functions of inhibitory receptor:ligand systems in cancer immune evasion.
Recommended Citation
Ibrahim, Mary, "Regulation of natural killer cell responses by myeloid-derived suppressor cells in mouse mammary tumors" (2023). Electronic Theses and Dissertations. 9268.
https://scholar.uwindsor.ca/etd/9268