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

Abstract

The therapeutic armamentarium of metastatic Renal Cell Carcinoma (mRCC) has consistently expanded in recent years, with the introduction of VEGF/VEGFR (Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor) inhibitors, mTOR (mammalian Target Of Rapamycin) inhibitors and Immune Checkpoint (IC) inhibitors. Currently, for the first-tline treatment of mRCC it is possible to choose between a VEGFR-TKI (VEGFR-Tyrosine Kinase Inhibitor) monotherapy, an ICI-ICI (Immune Checkpoint Inhibitor) combination and an ICI-VEGFRTKI combination. However, a consistent part of patients does not derive benefit from first-line therapy with ICIs; moreover, the use of combination regimens exposes patients to significant toxicities. Therefore, there is a critical need to develop prognostic and predictive biomarkers of response to VEGFR-TKIs and ICIs, and measurement of serum IL-8 is emerging as a potential candidate in this field. Recent retrospective analyses of large phase II and phase III trials found that elevated baseline serum IL-8 correlated with higher levels of tumor and circulating immunosuppressive myeloid cells, decreased T cell activation and poor response to treatment. These findings must be confirmed in prospective clinical trials; however, they provide evidence for a potential use of serum IL-8 as biomarker of resistance to VEGFR-TKIs and ICIs. Considering the amount of new agents and treatment regimens which are transforming the management of metastatic renal cell carcinoma, serum IL-8 could become a precious resource in tailoring the best therapy for each individual patient with the disease.

Keywords: IL-8; anti-angiogenic agent; biomarker of resistance; immune checkpoint inhibitors; kidney cancer.

Figure 1

Principal mechanisms involved in IL-8-induced resistance to ICI and anti-angiogenic TKI.