Interleukin-1 receptor 8 deficiency enhances the anti-tumour activity of doxorubucin and reduces cardiotoxicity

Abstract Background Chemo-immunotherapy, combining anthracyclines like Doxorubicin (Doxo) with immune checkpoint inhibitors (ICI), enhances immunogenic cell death and tumor-specific immune responses against different types of cancer [1]. It increases the risk of severe side effects, such as inflammation, hepatotoxicity, and T cell-mediated cardiotoxicity [2]. Interleukin-1 (IL-1) plays a key role in both cancer- and cardiac-related inflammation. IL-1 receptor 8 (IL-1R8), a negative regulator of IL-1 and TLR signaling, functions as an IC for NK and CD8+ cells, enhancing anti-tumor immunity in murine models [3]. To explore IL-1R8 as a novel IC, we investigated the role and potential side effects of its deficiency in combination with chemotherapy. Methods We investigated the impact of IL-1R8 deficiency on tumor growth and cardiac toxicity in response to Doxo treatment. Wild-type (wt) and Il1r8-/- mice were subcutaneously transplanted with FS6 fibrosarcoma cells and treated with high or low (20-10 mg/kg) Doxo concentration. Tumor growth was monitored and immune infiltration was analyzed. Cardiac function and fibrosis, immune infiltration, and inflammation were examined in cardiac tissue. Results The high-dose regimen completely eradicated the tumor in both genotypes, while low-dose Doxo significantly reduced tumor size in Il1r8-/- mice, accompanied by more mature CD8+ T cells, compared to wt mice. High-dose Doxo impaired cardiac function, with no genotype differences, indicating that IL-1R8 blockade does not impact on cardiotoxicity. In contrast with the hypothesis, Il1r8-/- mice exhibited reduced cardiac fibrosis, lower inflammation, and fewer T cells in cardiac tissue after Doxo treatment, compared to wt counterpart. Co-culture experiments (CD4+Th1 cells plus cardiac fibroblasts or macrophages) revealed that Il1r8-/- Th1 cells had reduced pro-fibrotic and inflammatory activity compared to wt cells, in line with previous study reporting MyD88 is a regulator of cardiac fibrosis through modulation of T-Cell activation. Conclusions Our results show that IL-1R8 targeting enhances the anti-tumor activity of Doxo, while reducing cardiotoxicity and fibrotic effects of CD4+ T cells.