Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells

TLDR

The study investigates whether eliminating CD4⁺/CD25⁺ regulatory T cells with DAB(389)IL‑2 can enhance the immunostimulatory efficacy of tumor RNA‑transfected dendritic cell vaccines. The authors used the recombinant IL‑2 diphtheria toxin conjugate DAB(389)IL‑2 to selectively deplete CD25‑expressing Tregs from patient peripheral blood mononuclear cells. DAB(389)IL‑2 selectively removes Tregs without harming other cell subsets, reduces peripheral Tregs in metastatic renal cell carcinoma patients, abrogates Treg‑mediated suppression, and when combined with RNA‑transfected DC vaccination markedly boosts tumor‑specific T‑cell responses, indicating that Treg depletion may potentiate antitumor immunity.

Abstract

In this study, we investigated whether elimination of CD4+/CD25+ Tregs using the recombinant IL-2 diphtheria toxin conjugate DAB(389)IL-2 (also known as denileukin diftitox and ONTAK) is capable of enhancing the immunostimulatory efficacy of tumor RNA-transfected DC vaccines. We show that DAB(389)IL-2 is capable of selectively eliminating CD25-expressing Tregs from the PBMCs of cancer patients without inducing toxicity on other cellular subsets with intermediate or low expression of CD25. DAB(389)IL-2-mediated Treg depletion resulted in enhanced stimulation of proliferative and cytotoxic T cell responses in vitro but only when DAB(389)IL-2 was omitted during T cell priming. DAB(389)IL-2 significantly reduced the number of Tregs present in the peripheral blood of metastatic renal cell carcinoma (RCC) patients and abrogated Treg-mediated immunosuppressive activity in vivo. Moreover, DAB(389)IL-2-mediated elimination of Tregs followed by vaccination with RNA-transfected DCs significantly improved the stimulation of tumor-specific T cell responses in RCC patients when compared with vaccination alone. Our findings may have implications in the design of immune-based strategies that may incorporate the Treg depletion strategy to achieve potent antitumor immunity with therapeutic impact.