Predictive value of CXCL10 for the occurrence of immune‐related adverse events in patient with renal cell carcinoma

Abstract

Immune checkpoint inhibitors (ICIs) have recently improved the prognosis of various cancers. By contrast, some immune-related adverse events (irAEs) caused by ICIs are fatal and have become problematic. The pathogenesis of irAEs remains unknown and must be elucidated to establish biomarkers. This study investigated plasma cytokine, chemokine, and anti-CD74 autoantibody levels in patients with renal cell carcinoma (RCC) and analyzed their association with irAEs. In a discovery cohort of 13 patients, plasma levels of chemokine (C-X-C motif) ligand (CXCL) 1, IL-17A, IL-1β, IL-6, IL-8, CXCL10, MCP-1, and TNFα were measured at baseline and post-dose 1. Only CXCL10, at post-dose 1 but not at baseline, was significantly associated with grade 2 or higher irAEs (P = 0.0413). Plasma CXCL10 levels were then measured at baseline and post-dose 1 in an extended cohort of 43 patients with RCC who received ICIbased treatment. Higher plasma CXCL10 levels both at baseline and post-dose1 were significantly associated with the occurrence of grade 2 or higher irAEs (P = 0.0246 and 0.0137, respectively). Plasma CXCL13 levels, which we measured in a previous study, were significantly higher in patients with grade 2 or higher irAEs at baseline but not at post-dose 1 (P = 0.0037 and 0.052, respectively). No significant association between plasma anti-CD74 autoantibody level and both irAE pneumonitis and any grade 2 or higher irAE was observed. In conclusion, plasma CXCL10 is significantly associated with the occurrence of irAEs in patients with RCC treated with ICIs. CXCL10 is a potential predictive and ontreatment biomarker for irAEs.

MIF and CD74 as Emerging Biomarkers for Immune Checkpoint Blockade Therapy

“…Furthermore, CD74 protein was expressed at much higher levels in the lungs of patients with ICB-induced pneumonitis compared to normal lung tissue, suggesting that the high expression of CD74 autoantibodies may have relevance in the mechanism of ICB-induced pneumonitis [93]. A follow-up study investigated CD74 autoantibody levels in the plasma of Japanese patients with renal cell carcinoma receiving ICB combination or monotherapy; in this work, CD74 autoantibody levels did not represent a predictive biomarker of pneumonitis irAE or higher-grade irAEs [94]. These conflicting reports suggest that further work is needed to establish whether CD74 can be a useful biomarker for irAE development.…”

Non-Invasive Predictive Biomarkers for Immune-Related Adverse Events Due to Immune Checkpoint Inhibitors

“…In two studies, elevated pretreatment levels of anti-CD74 and IL17 were found to be associated with pneumonitis in patients with solid tumors who received anti-PD1 with or without anti-CTLA-4 ICIs. However, another study by Miura et al did not find this association [ 64 , 106 , 109 ].…”

“…No association [15] ↓ risk [118] Pulmonary Pneumonitis Absolute eosinophil count ≥125 ↑ risk [119] White blood cell count ↑ risk [120] Absolute neutrophil count ↓ risk [120] Neutrophil-lymphocyte ratio No association [120], ↓ risk [100] Low IFN-γ ↑ risk [121] IL17 and anti-CD74 levels Conflicting results: ↑ risk [106,109] Not associated [64] HLA-B35 and HLA-DRB1*11 haplotype ↑ risk [122] HLA-B*35:01 ↑ risk [34] Table 3. Cont.…”

“…Increased levels of CXCL10 and CXCL13 at baseline, but not of IL6 or IL8, were associated with grade ≥2 irAEs in patients with renal cell carcinoma [ 64 ]. Another study showed that an increase in CXCL10 and decrease in IL10 were associated with the development of an irAE in malignant melanoma and NSCLC [ 57 ].…”