Maximilian Möller ¹ Vanessa Orth ¹ Viktor Umansky ^2,3,4 Svetlana Hetjens ⁵ Volker Braun ⁶ Christoph Reissfelder ^1,4 Julia Hardt ¹ Steffen Seyfried ^1*

• ¹ Department of Surgery, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany
• ² Department of Dermatology, Venereology and Allergology, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Baden-Württemberg, Germany
• ³ Skin Cancer Unit, German Cancer Research Center, Heidelberg, Baden-Württemberg, Germany
• ⁴ DKFZ-Hector Cancer Institute, University Medical Centre Mannheim, Mannheim, Germany
• ⁵ Department of Medical Statistics, Biomathematics and Information Processing, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Baden-Württemberg, Germany
• ⁶ Department of Library and Information Sciences, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Baden-Württemberg, Germany

Immunotherapeutic approaches, including immune checkpoint inhibitor (ICI) therapy, are increasingly recognized for their potential. Despite notable successes, patient responses to these treatments vary significantly. The absence of reliable predictive and prognostic biomarkers hampers the ability to foresee outcomes. This meta-analysis aims to evaluate the predictive significance of circulating myeloid-derived suppressor cells (MDSC) in patients with solid tumors undergoing ICI therapy, focusing on progression-free survival (PFS) and overall survival (OS).A comprehensive literature search was performed across PubMed and EMBASE from January 2007 to November 2023, utilizing keywords related to MDSC and ICI. We extracted hazard ratios (HRs) and 95% confidence intervals (CIs) directly from the publications or calculated them based on the reported data. A hazard ratio greater than 1 indicated a beneficial effect of low MDSC levels. We assessed heterogeneity and effect size through subgroup analyses. Our search yielded 4,023 articles, of which 17 studies involving 1,035 patients were included. The analysis revealed that patients with lower levels of circulating MDSC experienced significantly improved OS (HR=2.13 [95% CI 1.51-2.99]) and ) in response to ICI therapy. Notably, heterogeneity across these outcomes was primarily attributed to differences in polymorphonuclear MDSC (PMN-MDSC) subpopulations and varying cutoff methodologies used in the studies. The monocytic MDSC (M-MDSC) subpopulation emerged as a consistent and significant prognostic marker across various subgroup analyses, including ethnicity, tumor type, ICI target, sample size, and cutoff methodology.Our findings suggest that standardized assessment of MDSC, particularly M-MDSC, should be integral to ICI therapy strategies. These cells hold the promise of identifying patients at risk of poor response to ICI therapy, enabling tailored treatment approaches. Further research focusing on the standardization of markers and validation of cutoff methods is crucial for integrating MDSC into clinical practice.