ScRNAseq of Kaede red+ CD45+ cells from draining-lymph nodes of YUMMER1.7 tumors day 21 post implantation

ABSTRACT: Successful neoadjuvant immune checkpoint blockade (ICB) therapy depends on the maintenance of a pool of stem-like CD8+ T cells that are enriched in tumor-draining lymph nodes (LN). Upon ICB, stem-like CD8+ T cells activate and proliferate to generate effector T cells that seed the intratumoral response. Yet, how the stem-like niche is maintained over time in cancer remains poorly understood. Here, we identify a continuous lymphatic circuit that sustains the stem-like CD8+ T cell pool. Using photoconvertible fate-mapping, we demonstrate that effector CD8+ T cells egress from the tumor microenvironment via tumor-associated lymphatic vessels, and migrate back to the draining LN. These tumor-specific, migratory effector T cells avoid chronic antigen stimulation in the tumor, re-express the transcription factor associated with self-renewal, TCF1, and subsequently enter a stem-like state in the LN. We find that chronic antigen presentation in LNs by dendritic cells drives the local proliferation and transient residence of tumor-egressing T cells thereby inflating the LN stem-like population. Consequently, maintenance of stem-like T cells and ICB response depends on constitutive lymphatic transport, which sustains both effector egress and antigen presentation in the LN. Finally, we find that metastasis disrupts the stem-like LN niche in patients and impairs response to ICB in mice. We, therefore, define a continuous, peripheral lymphatic circuit that recycles tumor-experienced effector T cells to fuel durable systemic anti-tumor immune responses, providing mechanistic insight into the enhanced efficacy of neoadjuvant immunotherapy and highlighting the importance of preserving lymphatic transport for optimal cancer immunotherapy outcomes.

ORGANISM(S): Mus musculus

PROVIDER: GSE322572 | GEO | 2026/08/03

REPOSITORIES: GEO