Interleukin-8 and its role as a potential biomarker of resistance to immune checkpoint inhibitors in metastatic renal cell carcinoma

Interleukin-8 (IL-8) was originally described as a pro-inflammatory chemokine whose major role is the attraction of polymorphonuclear cells to the site of infection. However, it was found that tumours frequently co-opt the production of this chemokine, which in malignant contexts is involved in different pro-tumorigenic processes, including 1) cancer cell growth and survival, 2) stimulation of angiogenesis and 3) recruitment of myeloid cells endowed with the ability to immunosuppress and locally provide growth factors. IL-8 up-regulation was shown to confer resistance to chemotherapeutic agents and targeted agents, and recently its role in resistance to immune checkpoint inhibitors has been investigated. Immune checkpoint inhibitors, despite unprecedented clinical activity displayed in several types of cancer, including renal cell carcinoma, provide prolonged benefits in only a minority of treated patients, while exposing them to a significant amount of toxic adverse events. Development of biomarkers able to predict therapeutic response to these agents is a major area of research, and measurement of serum IL-8 is emerging as a new potential candidate. Variations of on-treatment serum IL-8 were able to predict response to immune checkpoint inhibitors in small cohorts of patients, and recent retrospective analyses of large ICI phase II and phase III trials found that elevated baseline serum IL-8 correlated with higher levels of tumour and circulating immunosuppressive myeloid cells, decreased T cell responsiveness and poor response to ICI treatment. These findings must be confirmed in prospective ICI clinical trials; however, they provide evidence for a potential use of serum IL-8 as biomarker of resistance to ICI. In consideration of the amount of new agents and treatment regimens which are transforming the management of metastatic renal cell carcinoma, serum IL-8 might become a precious resource in tailoring the best therapy for each individual patient with the disease.