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

<p><strong>BACKGROUND: </strong>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.</p><p><strong>METHODS: </strong>This 'cytokine problem' can be solved by use of AcTakines (<u>Ac</u>tivity-on-<u>Ta</u>rget cyto<u>kines</u>), which represent fusions between low-activity cytokine mutants and cell type-specific single-domain antibodies. AcTakines deliver cytokine activity to <em>a priori</em> 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.</p><p><strong>RESULTS: </strong>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.</p><p><strong>CONCLUSIONS: </strong>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.</p>