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

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          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.

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          Most cited references26

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          Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15.

          Proliferation of memory-phenotype (CD44hi) CD8+ cells induced by infectious agents can be mimicked by injection of type I interferon (IFN I) and by IFN I-inducing agents such as lipopolysaccharide and Poly I:C; such proliferation does not affect naive T cells and appears to be TCR independent. Since IFN I inhibits proliferation in vitro, IFN I-induced proliferation of CD8+ cells in vivo presumably occurs indirectly through production of secondary cytokines, e.g., interleukin-2 (IL-2) or IL-15. We show here that, unlike IL-2, IL-15 closely mimics the effects of IFN I in causing strong and selective stimulation of memory-phenotype CD44hi CD8+ (but not CD4+) cells in vivo; similar specificity applies to purified T cells in vitro and correlates with much higher expression of IL-2Rbeta on CD8+ cells than on CD4+ cells.
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            The role of interleukin-2 during homeostasis and activation of the immune system.

            Interleukin-2 (IL-2) signals influence various lymphocyte subsets during differentiation, immune responses and homeostasis. As discussed in this Review, stimulation with IL-2 is crucial for the maintenance of regulatory T (T(Reg)) cells and for the differentiation of CD4(+) T cells into defined effector T cell subsets following antigen-mediated activation. For CD8(+) T cells, IL-2 signals optimize both effector T cell generation and differentiation into memory cells. IL-2 is presented in soluble form or bound to dendritic cells and the extracellular matrix. Use of IL-2 - either alone or in complex with particular neutralizing IL-2-specific antibodies - can amplify CD8(+) T cell responses or induce the expansion of the T(Reg) cell population, thus favouring either immune stimulation or suppression.
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              IL-2: the first effective immunotherapy for human cancer.

              The ability of IL-2 to expand T cells with maintenance of functional activity has been translated into the first reproducible effective human cancer immunotherapies. The administration of IL-2 can lead to durable, complete, and apparently curative regressions in patients with metastatic melanoma and renal cancer. The growth of large numbers of tumor-infiltrating lymphocytes with in vitro anti-cancer activity in IL-2 has led to the development of cell transfer therapies that are highly effective in patients with melanoma. The genetic modification of T cells with genes encoding αβ TCRs or chimeric Ag receptors and the administration of these cells after expansion in IL-2 have extended effective cell transfer therapy to other cancer types.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                17 August 2022
                2022
                : 13
                Affiliations
                [1] 1 Immune Regulation Department, Centro de Inmunología Molecular , Havana, Cuba
                [2] 2 Division of Integrative Biosciences and Biotechnology, Pohang University of Science 12 and Technology (POSTECH) , Pohang, South Korea
                [3] 3 Instituto de Medicina Molecular, Faculdade de Medici na da Universidade de Lisboa , Lisbon, Portugal
                Author notes

                Edited by: Diana Boraschi, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Science (CAS), China

                Reviewed by: Cosima T Baldari, University of Siena, Italy; Luciana D'apice, National Research Council (CNR), Italy

                *Correspondence: Tania Carmenate, carmenate@ 123456cim.sld.cu

                †Deceased

                This article was submitted to Cytokines and Soluble Mediators in Immunity, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2022.974188
                9428827
                a065cb75-4d18-46d2-a3d3-078175483ee2
                Copyright © 2022 Carmenate, Montalvo, Lozada, Rodriguez, Ortiz, Díaz, Avellanet, Kim, Surh, Graça and León

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 3, Tables: 0, Equations: 0, References: 26, Pages: 9, Words: 4540
                Categories
                Immunology
                Original Research

                Immunology
                il-2 mutein,treg,cancer therapy,cd8+ t cells,tme
                Immunology
                il-2 mutein, treg, cancer therapy, cd8+ t cells, tme

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