The combined use of tocilizumab (TCZ) and immune checkpoint inhibitors (ICIs) in cancer treatment is gaining attention, but preclinical studies are lacking. Our study aims to investigate the synergistic anti-tumor effect of TCZ combined with ICIs and its role in treating immune-related adverse events (irAEs). The clinical significance of high interleukin-6 (IL-6) expression in tumor patients was analyzed from the Cancer Genome Atlas (TCGA) database. The expression levels of IL-6 were compared before and during the onset of ICIs-associated myocarditis patients. ICIs-related myocardial inflammatory injury and therapeutic lung cancer models were constructed in C57BL/6 J mice using murine-derived programmed death-1 (PD-1) inhibitors alone or in combination with TCZ. Possible inflammatory mechanisms were proposed and validated. The anti-tumor effects and mechanisms of both drugs in combination were assessed. Patients with high IL-6 expression had a poor prognosis, and those with ICIs-associated myocarditis exhibited elevated IL-6 from baseline. In the PD-1 inhibitors-associated myocardial inflammatory injury mouse model, the levels of IL-6 in the blood and cardiac tissues were significantly elevated. TCZ ameliorated immune myocardial inflammatory injury by inhibiting the IL-6/janus kinase 2 (JAK2)/signal transducer and activator of the transcription 3 (STAT3) pathway. The group treated with PD-1 inhibitors combined with TCZ showed significantly slower tumor growth than that treated with PD-1 inhibitors alone. TCZ resisted tumor growth by inhibiting the IL-6-JAK2-STAT3 pathway. By targeting the IL-6-JAK2-STAT3 pathway, TCZ can alleviate PD-1 inhibitors-associated myocardial inflammatory injury mediated by M1-polarized macrophages and plays a synergistic anti-tumor role by inhibiting lung cancer cell proliferation.
Keywords: IL-6; Immune checkpoint inhibitors; Myocardial inflammatory injury; Tocilizumab.
© 2024. The Author(s).