CD25-Treg-depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity

Solomon, Isabelle; Amann, Maria; Goubier, Anne; Vargas, Frederick Arce; Zervas, Dimitrios; Chen, Qing; Henry, Jake Y.; Ghorani, Ehsan; Akarca, Ayse U.; Marafioti, Teresa; Śledzińska, Anna; Sunderland, Mariana Werner; Demane, Dafne Franz; Clancy, Joanne Ruth; Georgiou, Andrew; Salimu, Josephine; Merchiers, Pascal; Brown, Mark; Flury, Reto; Eckmann, Jan; Murgia, Claudio; Sam, Johannes; Jacobsen, Björn; Marrer-Berger, Estelle; Boetsch, Christophe; Belli, Sara; Leibrock, Lea; Benz, J.; Koll, Hans; Sutmuller, Roger P.M.; Peggs, Karl S.; Quezada, Sergio A.

doi:10.1038/s43018-020-00133-0

Cited by 104 publications

(67 citation statements)

References 45 publications

(46 reference statements)

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“…Anti-CTLA-4 antibody, anti-CD25 antibody, or anti-CCR4 antibody are good candidates for Treg cell depletion (122). An anti-human CD25 antibody (RG6292) monotherapy as well as a combination of RG6292 with anti-PD-L1 antibody showed Treg cell depletion and inhibited tumor growth in mice models (123). Anti-CCL2 or anti-CCR2 antibody has been tested in clinical trials because CCL2 attracts TAM via CCR2 into local tumors and suppresses cytotoxic T cells (76,124,125).…”

Section: Therapy Targeting Emt-induced Immunosuppressionmentioning

confidence: 99%

Tumor Immune Microenvironment during Epithelial–Mesenchymal Transition

Taki

Abiko

Ukita

et al. 2021

Clinical Cancer Research

155

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Epithelial-mesenchymal transition (EMT) has been shown to play a critical role in tumor development from initiation to metastasis. EMT could be regarded as a continuum, with intermediate hybrid epithelial and mesenchymal phenotypes having high plasticity. Classical EMT is characterized by the phenotype change of epithelial cells to cells with mesenchymal properties, but EMT is also associated with multiple other molecular processes, including tumor immune evasion. Some previous studies have shown that EMT is associated with the cell number of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs), and the expression of immune checkpoints, such as programmed cell death-ligand 1, in several cancer types. At the molecular level, EMT transcriptional factors, including Snail, Zeb1, and Twist1, produce or attract immunosuppressive cells or promote the expression of immunosuppressive checkpoint molecules via chemokine production, leading to a tumor immunosuppressive microenvironment. In turn, immunosuppressive factors induce EMT in tumor cells. This feedback loop between EMT and immunosuppression promotes tumor progression. For therapy directly targeting EMT has been challenging, the elucidation of the interactive regulation of EMT and immunosuppression is desirable for developing new therapeutic approaches in cancer. The combination of immune checkpoint inhibitors (ICIs) and immunotherapy targeting immunosuppressive cells could be a promising therapy for EMT.Research.

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Section: Therapy Targeting Emt-induced Immunosuppressionmentioning

confidence: 99%

Tumor Immune Microenvironment during Epithelial–Mesenchymal Transition

Taki

Abiko

Ukita

et al. 2021

Clinical Cancer Research

155

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“…Interestingly, daclizumab, an anti-CD25 monoclonal antibody, was able to decrease and reprogram Tregs without unleashing significant autoimmunity in breast cancer patients, although lowering effector T (Teff) function due to IL-2 signaling blockade on these cells [ 35 ]. Moreover, the group of Quezada SA recently developed a CD25-blocking monoclonal antibody with an engineered Fc fragment (anti-CD25 NIB ), showing Treg depletion while conserving IL-2/STAT5 signaling on Teff [ 36 ]. Other molecules overexpressed by Tregs such as CCR4, CCR8, CTLA-4, OX40 and 4-1BB could also be proposed as targets [ 37 , 38 ].…”

Section: Future Strategies and Discussionmentioning

confidence: 99%

Hyperprogressive Disease: Main Features and Key Controversies

Arasanz

Zuazo

Bocanegra

et al. 2021

IJMS

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Along with the positioning of immunotherapy as a preferential treatment for a wide variety of neoplasms, a new pattern of response consisting in a sudden acceleration of tumor growth has been described. This phenomenon has received the name of “hyperprogressive disease”, and several definitions have been proposed for its identification, most of them relying on radiological criteria. However, due to the fact that the cellular and molecular mechanisms have not been elucidated yet, there is still some debate regarding whether this fast progression is induced by immunotherapy or only reflects the natural course of some highly aggressive neoplasms. Moreover, contradictory results of trials including patients with different cancer types suggest that both the incidence, the associated factors and the implications regarding prognosis might differ depending on tumor histology. This article intends to review the main publications regarding this matter and critically approach the most controversial aspects.

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“…The targets should be either exclusively expressed or highly enriched in intratumoral Tregs, preferably on the surface. synergistically enhancing an ICI therapy but without overt immune responses (55).…”

Section: Therapeutic Targets To Specifically Deplete Intratumoral Tregsmentioning

confidence: 99%

The Impact of Tregs on the Anticancer Immunity and the Efficacy of Immune Checkpoint Inhibitor Therapies

et al. 2021

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Although cancers arise from genetic mutations enabling cells to proliferate uncontrollably, they cannot thrive without failure of the anticancer immunity due in a large part to the tumor environment's influence on effector and regulatory T cells. The field of immune checkpoint inhibitor (ICI) therapy for cancer was born out of the fact that tumor environments paralyze the immune cells that are supposed to clear them by activating the immune checkpoint molecules such as PD-1. While various subsets of effector T cells work collaboratively to eliminate cancers, Tregs enriched in the tumor environment can suppress not only the native anticancer immunity but also diminish the efficacy of ICI therapies. Because of their essential role in suppressing autoimmunity, various attempts to specifically deplete tumor-associated Tregs are currently underway to boost the efficacy of ICI therapies without causing systemic autoimmune responses. A better understanding the roles of Tregs in the anti-cancer immunity and ICI therapies should provide more specific targets to deplete intratumoral Tregs. Here, we review the current understanding on how Tregs inhibit the anti-cancer immunity and ICI therapies as well as the advances in the targeted depletion of intratumoral Tregs.

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CD25-Treg-depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity

Cited by 104 publications

References 45 publications

Tumor Immune Microenvironment during Epithelial–Mesenchymal Transition

Tumor Immune Microenvironment during Epithelial–Mesenchymal Transition

Hyperprogressive Disease: Main Features and Key Controversies

The Impact of Tregs on the Anticancer Immunity and the Efficacy of Immune Checkpoint Inhibitor Therapies

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