PT - JOURNAL ARTICLE AU - Bram Van Den Eeckhout AU - Leander Huyghe AU - Sandra Van Lint AU - Elianne Burg AU - Stéphane Plaisance AU - Frank Peelman AU - Anje Cauwels AU - Gilles Uzé AU - Niko Kley AU - Sarah Gerlo AU - Jan Tavernier TI - Selective IL-1 activity on CD8<sup>+</sup> T cells empowers antitumor immunity and synergizes with neovasculature-targeted TNF for full tumor eradication AID - 10.1136/jitc-2021-003293 DP - 2021 Nov 01 TA - Journal for ImmunoTherapy of Cancer PG - e003293 VI - 9 IP - 11 4099 - http://jitc.bmj.com/content/9/11/e003293.short 4100 - http://jitc.bmj.com/content/9/11/e003293.full SO - J Immunother Cancer2021 Nov 01; 9 AB - 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.Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as online supplemental information.