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TY  - THES
AU  - Bharadwaj, Sraddha S
TI  - Early intestinal neoplasia induces a local immunosuppressive environment through macrophage-regulatory T cell interactions
PB  - RWTH Aachen University
VL  - Dissertation
CY  - Aachen
M1  - RWTH-2025-08803
SP  - 1 Online-Ressource : Illustrationen
PY  - 2025
N1  - Veröffentlicht auf dem Publikationsserver der RWTH Aachen University
N1  - Dissertation, RWTH Aachen University, 2025
AB  - Colorectal cancer (CRC) develops through a stepwise process beginning with early epithelial transformation and immune reprogramming. However, the immunological events that define this initial phase remain poorly understood. Using a genetically engineered mouse model in which continuous Wnt signaling drives early intestinalneoplasia, we investigated how localized tumoral changes reshape immune cell populations within the intestine and the liver. Particularly, we wanted to focus on how tumor regulatory T cells (Tregs) modulate CD8+ T cells and which immune cells control tumor Tregs in the intestine. We also investigated alterations in the immune cellpopulation in the liver upon intestinal neoplasia. We observed that tumor Tregs control the accumulation of activated CD8+ T cells, since we observed increased frequencies of activated CD8+ T cells when tumor Tregs did not accumulate in a model of MC38 tumor cell transplantation. Additionally, single-cell RNA sequencing showed that macrophages and dendritic cells (DCs) strongly respond to neoplasia, while flow cytometry demonstrated a parallel accumulation of these cells in the intestine. Multiplex immunofluorescence images suggested that macrophages and tumor Tregs interact with each other, and bone marrow chimeras revealed a role for antigen presentation by macrophages in promoting tumor Treg accumulation. On the other hand, tumor Treg frequencies were also increased in the mesenteric lymph node, however, the contribution of DCs in tumor Treg accumulation appeared to be minimal. Re-analysis of the transcriptomic data from macrophages and DCs revealed that upon neoplasia, both cell types express higher levels of Plet1, which has been previously linked to tissue repair. Anearly immune response was also observed in the liver since we observed infiltration of hepatic monocytes upon intestinal neoplasia. Our results suggest that tumor Treg-myeloid cell interaction controls inflammatory responses during intestinal neoplasia. This was also accompanied by changes in the liver, which indicate potential priming forfuture tumor cell seeding. Collectively, these findings shed light on the immune changes that occur in the earliest stages of colorectal cancer and may be useful in the development of therapeutic strategies aimed at intercepting tumor progression along the gut-liver axis even before it is fully established.
LB  - PUB:(DE-HGF)11
DO  - DOI:10.18154/RWTH-2025-08803
UR  - https://publications.rwth-aachen.de/record/1020150
ER  -