Systemic inflammation shapes clinical outcomes in response to immune checkpoint blockade treatment: moving toward optimizing antitumor immunity

BACKGROUND: Immune checkpoint blockade (ICB) treatment may induce durable disease remission, but only in a minority of patients with cancer. One important question is how to identify patients who may benefit from ICB treatment. ICB treatment relies on unleashing patients’ pre-existing immune responses. Focusing on the key components of immune response, this study proposes the neutrophil-to-lymphocyte ratio (NLR) as a simplified indicator of patients’ immune status to predict ICB treatment outcomes. METHODS: This study analyzed a large pan-cancer cohort of 16 cancer types, including 1714 patients with cancer who received ICB treatment. Clinical outcomes in response to ICB treatment were measured by overall survival (OS), progression-free survival (PFS), objective response rate, and clinical benefit rate. The non-linear relationships of NLR with OS and PFS were investigated by a spline-based multivariate Cox regression model. A total of 1000 randomly resampled cohorts were bootstrapped to estimate the variability and reproducibility of NLR-related ICB responses. RESULTS: By interrogating a clinically representative cohort, this study revealed a previously unreported finding that the pretreatment NLR levels were associated with ICB treatment outcomes in a U-shaped dose-dependent manner rather than a linear manner. An NLR range between 2.0 and 3.0 was remarkably associated with optimal ICB treatment outcomes, including increased patient survival, delayed disease progression, improved treatment response, and significant clinical benefit. Comparatively, either decreasing (< 2.0) or increasing (>3.0) NLR levels were indicators of worse ICB treatment outcomes. Furthermore, this study presents a comprehensive landscape of NLR-related ICB treatment outcomes across different patient populations defined by demographics, baseline characteristics, treatment, cancer-type-specific ICB responsiveness, and individual cancer type. CONCLUSIONS: The NLR range from 2.0 to 3.0 might indicate an optimal balance between innate (neutrophils) and adaptive (lymphocytes) immune responses that potentiates antitumor immunity, which was observed in only 18.6% of patients. A majority of patients showed decreasing NLR (<2.00; 10.9% patients) or increasing NLR (>3.00; 70.5% patients), representing two distinct types of immune dysregulation associated with ICB resistance. This study translates routine blood tests into a precision medicine-based approach to immunotherapy, with important implications for clinicians in clinical decision-making as well as for regulatory agencies in drug approvals.