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

Abstract

BackgroundClinical 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.MethodsThis ‘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.ResultsIn 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.ConclusionsOur 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.

Mucosal immunization with an adenoviral vector vaccine confers superior protection against RSV compared to natural immunity

“…IL-1β is a hallmark cytokine of tissue inflammation ( 39 , 40 ) and particularly connected to T cell stimulating properties ( 41 – 43 ). Therefore, this cytokine was already used in several studies as adjuvant for example as mucosal adjuvant in flu vaccinations ( 16 , 44 ) or as T cell stimulus in cancer vaccines ( 45 – 47 ). IPS-1 was chosen as adjuvant candidate since the retinoic acid inducible gene I (RIG-I)-IPS-1 pathway plays an important role in innate immune sensing of viral infections including RSV ( 48 – 50 ) and the subsequent activation of adaptive immune responses ( 51 , 52 ) as exploited by the co-application of RIG-I agonists in vaccination settings ( 53 , 54 ).…”

Anti-Inflammatory Effects of the LK5 Herbal Complex on LPS- and IL-4/IL-13-Stimulated HaCaT Cells and a DNCB-Induced Animal Model of Atopic Dermatitis in BALB/c Mice

“…Next, HaCaT cells were stimulated with 1 μg/mL LPS for 24 h after treatment with the LK5 herbal complex at each concentration for 1 h. The LK5 herbal complex reduced NO production in a concentration-dependent manner and inhibited the expression of iNOS mRNA, which is involved in NO production and synthesis ( Figure 3 B,C). LPS is known to stimulate the production of inflammatory cytokines such as TNF-α, IL-1β, and IL-6 [ 37 , 38 , 39 ]. Therefore, we investigated whether the LK5 herbal complex inhibits inflammatory cytokine production.…”

“…This study observed the anti-inflammatory properties of the LK5 herbal complex in HaCaT cells stimulated with LPS and IL-4/IL-13. Inflammatory cytokines such as TNF-α, IL-6, and IL-1β are increased by LPS, which is known to promote inflammatory responses such as vasodilation and immune cell migration [ 37 , 38 , 39 ]. Recently, studies have shown that these cytokines can regulate the transcription factor STAT, which expresses several inflammatory genes [ 74 , 75 ].…”

Cancer genome and tumor microenvironment: Reciprocal crosstalk shapes lung cancer plasticity

“…As outlined above, there is ample evidence to suggest that cytokine networks govern immune evasion and foster the development of immunosuppressive T cells and TAMs within the TME ( Van Den Eeckhout et al, 2021 ; Van Den Eeckhout et al, 2020 ). However, it is still unclear how to tackle the TME cytokine milieu therapeutically in order to trigger strong and sustained antitumor responses in the majority of patients.…”