Selective IL-1 activity on CD8+ T cells empowers antitumor immunity and synergizes with neovasculature-targeted TNF for full tumor eradication - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal for Immunotherapy of Cancer Année : 2021

Selective IL-1 activity on CD8+ T cells empowers antitumor immunity and synergizes with neovasculature-targeted TNF for full tumor eradication

Stéphane Plaisance
Niko Kley
  • Fonction : Auteur

Résumé

Background: Clinical success of therapeutic cancer vaccines depends on the ability to mount strong and durable antitumor T cell responses. To achieve this, potent cellular adjuvants are highly needed. Interleukin-1β (IL-1β) acts on CD8+ T cells and promotes their expansion and effector differentiation, but toxicity and undesired tumor-promoting side effects hamper efficient clinical application of this cytokine. Methods: This 'cytokine problem' can be solved by use of AcTakines (Activity-on-Target cytokines), which represent fusions between low-activity cytokine mutants and cell type-specific single-domain antibodies. AcTakines deliver cytokine activity to a priori selected cell types and as such evade toxicity and unwanted off-target side effects. Here, we employ subcutaneous melanoma and lung carcinoma models to evaluate the antitumor effects of AcTakines. Results: In this work, we use an IL-1β-based AcTakine to drive proliferation and effector functionality of antitumor CD8+ T cells without inducing measurable toxicity. AcTakine treatment enhances diversity of the T cell receptor repertoire and empowers adoptive T cell transfer. Combination treatment with a neovasculature-targeted tumor necrosis factor (TNF) AcTakine mediates full tumor eradication and establishes immunological memory that protects against secondary tumor challenge. Interferon-γ was found to empower this AcTakine synergy by sensitizing the tumor microenvironment to TNF. Conclusions: Our data illustrate that anticancer cellular immunity can be safely promoted with an IL-1β-based AcTakine, which synergizes with other immunotherapies for efficient tumor destruction.
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hal-03427052 , version 1 (12-11-2021)

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Bram van den Eeckhout, Leander Huyghe, Sandra van Lint, Elianne Burg, Stéphane Plaisance, et al.. Selective IL-1 activity on CD8+ T cells empowers antitumor immunity and synergizes with neovasculature-targeted TNF for full tumor eradication. Journal for Immunotherapy of Cancer, 2021, 9, ⟨10.1136/jitc-2021-003293⟩. ⟨hal-03427052⟩
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