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
• Term: from 2022 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 499534188

• Final Report Year: 2024

Final Report Abstract

Aging has a profound impact on various aspects of health, including the development and progression of age-related diseases such as cancer. Cancer, including malignant melanoma, imposes a significant health burden on individuals aged 50 and older, with this age group bearing 90 % of the cancer mortality burden. There is also a notable gender disparity, with males experiencing an almost two-fold greater risk of mortality compared to females. These findings underscore the critical significance to get a better understanding of complex interplay between aging, sex, and tumor immunology. The majority of tumor infiltrating CD8 T cells are bystander cells and not responsive to tumor antigens. My preliminary data indicates a higher proportion of naïve-like CD8 bystander T cells in melanoma tumors of male patients and in the B16OVA mouse model in mid-aged mice, while T cells in females display a more cytotoxic or exhausted phenotype. Since, the intra-tumoral proliferation of activated CD8 cells was equal between sexes, I identified the tumor-draining lymph node as source for the higher rate of tumor-targeting CD8 T cells in females. Lymph nodes undergo a gradual age-related contraction that is characterized by a decline in size and the number of accommodated naïve T cells and with a predominance in males. My data suggests that the stronger decline of the T cell pool in mid-aged males is based on a disproportionate supply of newly generated T cells from the thymus and a loss of mature naïve CD8 T cells due to an enhanced loss of “naivety” and digerentiation towards a memory-like phenotype. The sex-biased digerences in the number of naïve CD8 T cells presumedly restrains the TCR diversity within a draining lymph node, which reduces the probability of tumor antigens being recognized and eliciting an egective anti-tumor immune response.

Publications

• Cancer cell plasticity and MHC-II–mediated immune tolerance promote breast cancer metastasis to lymph nodes. Journal of Experimental Medicine, 220(9).
  Lei, Pin-Ji; Pereira, Ethel R.; Andersson, Patrik; Amoozgar, Zohreh; Van Wijnbergen, Jan Willem; O’Melia, Meghan J.; Zhou, Hengbo; Chatterjee, Sampurna; Ho, William W.; Posada, Jessica M.; Kumar, Ashwin S.; Morita, Satoru; Menzel, Lutz; Chung, Charlie; Ergin, Ilgin; Jones, Dennis; Huang, Peigen; Beyaz, Semir & Padera, Timothy P.
  
• Cancer immunotherapy responses persist after lymph node resection
  Zhou H., Baish J.W., O’Melia J.W., Darragh L.B., Specht E., Czapla J., Lei L., Menzel L., Rajotte J.J., Nikmaneshi M.R., Razavi M.S., Vander Heiden M.G., Ubellacker J.M., Munn L.L., Boland G.M., Cohen S., Karam S.D., Padera T.P.
  
• Lymphatic muscle cells are unique cells that undergo aging induced changes.
  Lei, Pin-Ji; Ruscic, Katarina J.; Roh, Kangsan; Rajotte, Johanna J.; O’Melia, Meghan J.; Bouta, Echoe M.; Marquez, Marla; Pereira, Ethel R.; Kumar, Ashwin S.; Arroyo-Ataz, Guillermo; Razavi, Mohammad S.; Zhou, Hengbo; Menzel, Lutz; Kumra, Heena; Duquette, Mark; Huang, Peigen; Baish, James W.; Munn, Lance L.; Ubellacker, Jessalyn M. ... & Padera, Timothy P.