DOI: 10.6084/m9.figshare.26779916.v1
title: Peripheral blood cytokines and outcomes with immune checkpoint blockade: a systematic review and meta-analysis

description: <b>Background:</b> Tumor-promoting inflammation and inflammatory cytokines are linked to immune checkpoint blockade (ICB) resistance. <b>Methods:</b> We assessed the associations between pre-treatment Interleukin-6 (IL-6), Interleukin-8 (IL-8) levels and on-treatment changes in IL-6, IL-8 and C-reactive protein (CRP) with ICB trial end points. <b>Results:</b> 27 studies representing 6,719 patients were included. Low pre-treatment IL-6 levels were associated with improved objective response rate (ORR) (odds ratio (OR) = 0.31 [0.18–0.55]) and better progression-free survival (PFS) (hazard ratio (HR) = 0.59 [0.48–0.72]) and overall survival (OS) [95% confidence interval (CI)] (HR = 0.42 [0.35–0.50]). Low pre-treatment IL-8 levels were associated with improved ORR (OR = 0.47 [0.36–0.61]) and better PFS (HR = 0.65 [0.58–0.74]) and OS (HR = 0.44 [0.39–0.51]). On-treatment decline in CRP was associated with improved ORR (OR = 0.18 [0.11–0.20]), PFS (HR = 0.40 [0.31–0.91]) and OS (HR = 0.48 [0.40–0.58]). <b>Conclusion:</b> Peripheral blood cytokines warrant further evaluation as enrichment and pharmacodynamic biomarkers for strategies targeting tumor-promoting inflammation. Measuring a substance called C-reactive protein (CRP) in the blood can help predict if cancer treatments that boost the immune system, like immune checkpoint blockers (ICB), will work. CRP levels are increased when there is inflammation in the body, helping cancer cells grow. IL-6 and IL-8 are related blood markers that are more specific to cancer cells and may improve our ability to predict if ICB will effectivity destroy cancer cells. Our study found that having lower levels of IL-6 and IL-8 before treatment and low levels of CRP during treatment might mean patients live longer and respond better to ICB treatments. Measuring IL-6 and IL-8 before treatment and CRP during treatment could help improve how doctors use ICB to treat cancer by managing inflammation that helps cancer grow. Our meta-analysis of 27 studies & 6,719 patients finds lower pre-treatment levels of IL-6/IL-8 and declines in C-reactive protein (CRP) levels during immune checkpoint blockade (ICB) predict better response to ICB therapy in solid tumors. Targeting inflammation may help overcome ICB resistance. Meta-analyses have established C-reactive protein (CRP) as a prognostic biomarker for solid tumor patients treated with immune checkpoint blockade (ICB). Inflammatory cytokines levels of IL-6 and IL-8 in the tumor microenvironment have been linked to poor outcomes with ICB and Interleukin-6 (IL-6) leads to CRP release from the liver. Our systematic review included 27 studies involving 6719 patients to evaluate the associations of both pre-treatment IL-6 and/or IL-8 levels and on-treatment changes in IL-6, Interleukin-8 (IL-8) and CRP levels with response to ICB. Low pre-treatment levels of IL-6 and IL-8 and declines in CRP levels during treatment were linked to better objective response rates and survival outcomes. Meta-regression analysis did not observe a correlation between IL-6, IL-8 and CRP cutoff values and survival. Our meta-analysis did not identify publication bias, included all high-quality studies, and identified sources of heterogeneity. Pretreatment IL-6 and IL-8 and on-treatment CRP levels may be attractive enrichment, or pharmacodynamic, biomarkers for strategies targeting tumor promoting inflammation to overcome ICB resistance. Integrating cytokine levels with other known biomarkers of ICB response may enhance predictive power and provide a more comprehensive biomarker panel for clinical use. Strategies targeting tumor-promoting inflammation are needed to extend the benefits of ICB to larger patient populations.