The antitumor effect induced by an IL-2 ‘no-alpha’ mutein depends on changes in the CD8+ T lymphocyte/Treg cell balance

Abstract

High doses of interleukin-2 (IL-2) have been used for the treatment of melanoma and renal cell carcinoma, but this therapy has limited efficacy, with a ~15% response rate. Remarkably, 7%–9% of patients achieve complete or long-lasting responses. Many patients treated with IL-2 experienced an expansion of regulatory T cells (Tregs), specifically the expansion of ICOS+ highly suppressive Tregs, which correlate with worse clinical outcomes. This partial efficacy together with the high toxicity associated with the therapy has limited the use of IL-2-based therapy. Taking into account the understanding of IL-2 structure, signaling, and in vivo functions, some efforts to improve the cytokine properties are currently under study. In previous work, we described an IL-2 mutein with higher antitumor activity and less toxicity than wtIL-2. Mutein was in silico designed for losing the binding capacity to CD25 and for preferential stimulation of effector cells CD8+ and NK cells but not Tregs. Mutein induces a higher anti-metastatic effect than wtIL-2, but the extent of the in vivo antitumor activity was still unexplored. In this work, it is shown that mutein induces a strong antitumor effect on four primary tumor models, being effective even in those models where wtIL-2 does not work. Furthermore, mutein can change the in vivo balance between Tregs and T CD8+ memory/activated cells toward immune activation, in both healthy and tumor-bearing mice. This change reaches the tumor microenvironment and seems to be the major explanation for mutein efficacy in vivo.

Treg Therapy for the Induction of Immune Tolerance in Transplantation—Not Lost in Translation?

“…Here, extending studies with the S4B6 IL-2 mab that blocks IL-2 binding to IL-2Rα (CD25) [ 66 ], IL-2 has been mutated to bind poorly to the α-chain of the high-affinity IL-2Rαβγ present on Tregs but retain binding for IL-2Rβγ, i.e., the low-affinity IL-2R found on CD8 and NK cells. Hence, like IL-2/S4B6 complexes, IL-2 muteins with poor binding to Tregs can be used to selectively stimulate CD8 cells and NK cells, thereby being useful for cancer immunotherapy [ 67 , 68 ]. Extending this approach, muteins prepared with reciprocal strong binding to IL-2Rα but limited affinity for IL-2Rβγ can be used for selective Treg expansion.…”

Transcriptional reprogramming by IL-2 variant generates metabolically active stem-like T cells

“…In this study, we optimized IL-2/IL-2R interactions in T cells by substituting IL-2/IL-15 with an engineered IL-2Rβγ agonist, rationally modified to abrogate IL-2Rα binding 26,27 (henceforth referred to as IL-2 variant; IL-2v). Using a comprehensive systems biology approach including mathematical modeling and high-dimensional analyses of metabolic tasks and gene regulatory network inference, we reveal that IL-2v alters T-cell fate decisions to drive a previously undescribed metabolically active stem-like T cell state (abbreviated TMAS) that differs from both natural IL-2-and IL-15-induced cell states.…”