IL-2 enhances ex vivo–expanded regulatory T-cell persistence after adoptive transfer

Abstract

As regulatory T cell (Treg) adoptive therapy continues to develop clinically, there is a need to determine which immunomodulatory agents pair most compatibly with Tregs to enable persistence and stabilize suppressor function. Prior work has shown that mechanistic target of rapamycin inhibition can increase the stability of thymic Tregs. In this study, we investigated the transcriptomic signatures of ex vivo–expanded Tregs after adoptive transfer in the setting of clinically relevant immunosuppression using a nonhuman primate (NHP) model as a prelude to future transplant studies. Here, we found that adding interleukin-2 (IL-2) to rapamycin in vivo supported a logarithmic increase in the half-life of adoptively transferred carboxyfluorescein diacetate succinimidyl ester–labeled, autologous NHP Tregs, effectively doubling the number of cells in the peripheral blood Treg compartment compared with Treg infusion when rapamycin was given alone. Using single-cell transcriptomics, we found that transferred ex vivo–expanded Tregs initially exhibit a gene expression signature consistent with an activated state. Moreover, those cells with the highest levels of activation also expressed genes associated with p53-mediated apoptosis. In contrast, transferred Tregs interrogated at day +20 posttransfer demonstrated a gene signature more similar to published profiles of resting Tregs. Together, these preclinical data further support combining IL-2 and rapamycin in vivo as adjunctive therapy for ex vivo–expanded adoptively transferred Tregs and suggest that the activation status of ex vivo–expanded Tregs is critical to their persistence.

Antigen Specificity Enhances Disease Control by Tregs in Vitiligo

“…The number of adoptively transferred Tregs was identified to enable a comparison to our earlier studies (21), where the 2x10 5 polyclonal Tregs controlled depigmentation in in the human Tyrosinase TCR Transgenic-HLA-A2 (h3TA2) mouse model between 3-9 weeks old mice. All groups received low dose of recombinant human IL-2 (3,000 IU) 3 times a week throughout the entire experiment to promote in vivo stimulation of adoptively transferred Tregs (45,46). Animals were maintained for 15 weeks and humanely euthanized.…”

Ex Vivo High Salt Activated Tumor-Primed CD4+T Lymphocytes Exert a Potent Anti-Cancer Response

“…Further, CAR-T cells are developed with generic specificity to cancer neo-antigens (off-the-shelf), but this approach would be difficult to generate specific T-cells for personalized use [ 42 ]. For bulk expansion, cytokines such as IL-2 have been shown to expand the immunosuppressive Treg phenotype of T-cells, thus limiting the long-term success of this strategy [ 43 ]. In this communication, we utilized a novel approach to expand the effector phenotype of CD4+T cells which retained their in vivo anti-cancer efficiency ( Figure 9 ).…”

Adoptive T Cell Therapy for Solid Tumors: Pathway to Personalized Standard of Care

“…IL-2 is a pleiotropic cytokine that induces cell-type specific responses. For example, IL-2 is not only involved in the differentiation and homeostasis of Tregs but it also promotes the differentiation of effector CD8+ T cells and increased synthesis of effector molecules [ 44 , 58 , 59 ]. Since the initial clinical trials in the 1980s, TIL-ACT protocols have incorporated the use of IL-2 in the ex vivo expansion phase [ 9 , 32 ].…”