Project Details
Projekt
Regression of high endothelial venules manifests sex dimorphism of lymph nodes during aging with implications to anti-tumor immune responses
Applicant
Dr. Lutz Menzel
Subject Area
Hematology, Oncology
Cell Biology
Cell Biology
Term
from 2022 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 499534188
Cancers of non-reproductive tissues occur at a higher frequency in males with a mortality rate twice as high compared to females. This disparity between women and men occurs all across the world, even when the data is adjusted for environmental risk factors and live style. The difference in anti-tumor immune responses is one determining factor of the sex-biased cancer incidence. However, how the innate and adaptive immune system engage with cancer as determined by sex and age is still poorly understood. My preliminary data show a regression of LTbR/NFkB-maintained high endothelial venules (HEV) and a subsequent decline of LN volume and cellularity that occurs in both sexes but earlier in live in males. I hypothesize that female gonadal hormones stimulate HEVs directly or via transcriptional regulation by secondary factors. Single-cell RNA sequencing data of LNs from middle-aged and older individuals revealed that osteopontin (OPN) is differentially expressed in HEV cells of females compared to males. Acting as an intracellular stabilizer of the NFkB pathway, OPN appears to be a promising candidate involved in HEV maintenance in female LNs. I further hypothesize that the smaller population size of naïve T cells in male LNs causes a more restricted TCR repertoire in tumor draining LNs, which might play a part in the inferior anti-tumor immunity and the male predominance in cancer incidence and mortality. In the proposed project, I will measure sex-disparities of LNs sizes, investigate sex and age-related mechanisms that dictate these differences and assess implications for anti-tumor immune responses.
DFG Programme
WBP Fellowship
International Connection
USA
