Poster Presentation 18th International Symposium on Dendritic Cells 2026

Intratumor mature DCs enriched in immunoregulatory molecules support local CD4+ Foxp3+ regulatory T cell activation (#248)

Claire Murat 1 2 , Shannon Geels 1 2 , Alexander Moshensky 1 2 , Francesco Marangoni 1 2
  1. Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, United States
  2. Institute for Immunology, University of California Irvine, Irvine, CA, United States

Conventional dendritic cells (cDCs) orchestrate the immune response against tumors by activating both effector and regulatory T cells. Among the two ontogenically distinct cDC subsets, cDC1 and cDC2, cDC1 are essential for initiating and maintaining antitumor responses by CD8+ and CD4+ effector T cells. However, the cDC subset responsible for activating tumor-associated T regulatory cells (Tregs) in the tumor environment remains unknown. Upon activation, both intratumoral cDC1 and cDC2 can acquire a state often referred to as “mature DCs enriched in immunoregulatory molecules” (mregDCs). These cells migrate to tumor-draining lymph nodes to prime CD4 and CD8 T cells or localize within tumor niches. However, their local functions within tumors remain poorly understood. MregDCs may exert both pro- and anti-tumor effects as they have been shown to form niches with Tregs in peri-lymphatic regions, while also supporting activated CD8 T cells in perivascular areas. To investigate their role, we developed a mouse model enabling specific depletion of mregDCs by crossing IL12bBFP-creERT2 mice with Rosa26LSL-DTA mice, leveraging the high expression of Il12b in mregDCs. We found that tamoxifen administration in FTY720-treated, MC38 tumor-bearing mice led to selective depletion of intratumoral mregDCs without affecting macrophages or other cDC subsets. While Treg numbers remained unchanged, their activation status was reduced, as indicated by decreased expression of Foxp3, Ki67, GITR, and ICOS. These findings suggest that mregDCs promote Treg activation and may contribute to immunosuppression in the tumor. Given that the spatial organization of mregDCs with their cellular partners likely shapes their function, and considering their ontogenetic heterogeneity, we will next investigate functional differences between cDC1-derived (mregDC1) and cDC2-derived (mregDC2) subsets using multiplexed spatial proteomics. Defining local tumor partners that support immunosuppressive Tregs or cytotoxic CD8 T cells will be instrumental in guiding new therapeutic strategies.