Finding the sweet spot: local Treg loss reprograms systemic antitumor immunity without breaking tolerance

Keywords

● Treg ablation

● Antitumor immunity

● Peripheral tolerance

● cDC2

Main Findings

High frequencies of tumor-infiltrating regulatory T (Treg) cells correlate with poor prognosis across multiple cancers. However, systemic Treg depletion disrupts peripheral tolerance and triggers severe autoimmunity, making selective targeting of Tregs a major therapeutic challenge. Effective strategies must therefore neutralize Treg-mediated immunosuppression while sparing systemic immune regulation.

In a recent preprint, Bockman et al. present compelling evidence that intratumoral Treg ablation alone is sufficient to control tumor growth without eliciting autoimmunity. Using Foxp3DTRmice, in which Tregs can be selectively depleted by diphtheria toxin (DT) administration, the authors demonstrate that local Treg depletion induces robust antitumor immunity against transplanted tumors without systemic immune pathology. Intratumoral Treg ablation led to pronounced activation of CD4⁺ and CD8⁺ T cells within the tumor microenvironment, but not in secondary lymphoid organs, underscoring the spatial specificity of the primary response.

Remarkably, local Treg ablation also induced an abscopal effect, restraining the growth of antigen-matched distal tumors while sparing mismatched ones—indicating T-cell-mediated systemic antitumor specificity. Mechanistically, primary tumor control depended on CD4⁺ T cells, whereas control of distant tumors required CD8⁺ T cells and dendritic cells (DCs). To dissect DC involvement, the authors generated Zbtb46DTR × Foxp3DTRmice, enabling concurrent depletion of conventional DCs (cDCs) and Tregs. Dual depletion completely abrogated both local and systemic tumor control, establishing cDCs as indispensable mediators of immunity following intratumoral Treg loss.

Unexpectedly, when Batf3⁻/⁻ × Foxp3DTR mice lacking cDC1s were treated with DT, tumor control remained intact, implicating cDC2s as the key antigen-presenting subset. Using MC38-mCherry cells to track tumor antigen uptake, the authors found that only cDC2s exhibited enhanced antigen capture upon Treg depletion. This finding was confirmed ex vivo, as Treg-depleted tumor cDC2s preferentially phagocytosed fluorescent beads.

Together, these results uncover a previously unrecognized cDC2–CD4⁺ T-cell axis that mediates local tumor control following Treg ablation, independent of CD8⁺ T-cell involvement. Crucially, this work delineates a mechanistic framework for achieving tumor-specific immune activation without compromising systemic tolerance. By defining the “sweet spot” of spatially restricted immune modulation, Bockman et al. illuminate a path toward therapeutic strategies that locally abrogate immune suppression while preserving systemic immune homeostasis.

Limitations

The authors concluded that cDC2s are the main APC population driving the antitumor effect upon Treg ablation by using the Zbtb46DTR mouse model to deplete both cDC1s and cDC2s and by using Batf3-/- mice to exclude cDC1s. The authors conclude that cDC2s are the main antigen-presenting players because Batf3-/- mice did not mitigate the antitumor effect. However, it is suggested that the authors prove their point using cDC2-specific mouse models, because Zbtb46DTR mice are also used to study mature DCs (mregDCs), and it is unclear whether the antitumor effect upon Treg depletion is uniquely driven by cDC2s, or mature DCs. Also, another limitation is the lack of a wildtype DT control as it is unclear whether some of the observed antitumor effects derive from a potential adjuvant effect of DT.

Significance/Novelty

This is a highly significant study that can potentially provide mechanistic insights that can be translated in the clinical setting to target a very important immune cell population. The cellular mechanisms proposed in this study are relatively novel, although the cDC2-CD4 T-cell axis upon Treg depletion has already been reported before.

Credit

Reviewed by Mehdi Chaib as part of a cross-institutional journal club between the Icahn School of Medicine at Mount Sinai, the University of Oxford, the Karolinska Institute, the University of Toronto, and the MD Anderson James P. Allison Institute.

The author declares no conflict of interests in relation to their involvement in the review.