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Intra-tumoral Treg Ablation Activates a CD4-NK Cell Axis to Control CD8 T cell Resistant Tumors

ABSTRACT: Tumors evade control by CD8+ T cells by losing MHC I expression, necessitating new approaches to improve immunotherapy. NK cells target MHC I-deficient cells but are insufficiently activated to control tumors without help. Here we uncovered a novel approach to control MHC I-deficient tumors by ablating Treg cells intratumorally, which incites potent antitumor NK cell responses without imparting lethal autoimmunity. IT-Treg ablation increased NK cell activation, maturation, expression of effector molecules, and anti-tumor cytotoxic activity. In this setting, conventional CD4+ T cells were required for NK cell activation, due to their production of IL-2 after interacting with conventional type 2 dendritic cells. These results demonstrate an opportunity to reinvigorate antitumor NK cell responses against tumors that evade CD8 T cell responses, by locally depleting Tregs. The findings also highlight the multicellular immunosuppression enforced by Tregs that extends beyond the control of CD8 T cell responses to tumors.

ORGANISM(S): Mus musculus

PROVIDER: GSE287581 | GEO | 2025/08/01

REPOSITORIES: GEO

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