# Combinatorial Analysis of CD4+Tregs, CD8+Teffs, and Inflammatory Indices Predict Response to ICI in ES-SCLC Patients

## TL;DR

This study shows that a blood-based immune profile can predict which lung cancer patients are more likely to benefit from immunotherapy.

## Contribution

A novel blood-based immune signature combining T cell ratios and inflammation markers is proposed to predict immunotherapy response in SCLC.

## Key findings

- Higher CD8+ T effector cells and lower Treg/Teff ratios correlate with longer survival in SCLC patients.
- Low Treg/Teff ratios are associated with low NLR and eosinophil levels before treatment.
- The immune profile is easily obtainable and could guide therapy decisions in clinical practice.

## Abstract

Small-cell lung cancer is a very aggressive form of lung cancer, and only a portion of patients benefit from new treatments that activate the immune system. Doctors currently lack simple tests that can show in advance which patients are more likely to respond. In this study, we examined routine blood measurements and specific immune cells circulating in the blood. We found that patients with a lower balance of certain regulatory immune cells compared with active immune cells, along with lower levels of inflammation markers, tended to live longer after starting immunotherapy. Our results suggest that a simple blood-based profile may help identify which patients are more likely to benefit from treatment, offering a practical tool for guiding therapy decisions and improving patient care.

Background: Small-cell lung cancer (SCLC) is an aggressive type of lung cancer, and several factors are currently used to predict poor outcomes, including performance status (PS), extensive-stage disease, male sex, advanced age, and elevated lactate dehydrogenase (LDH) levels. In this study, we aimed to explore the role of Tegs and inflammatory indices, such as CRP and NLR, in predicting response to immunotherapy. Methods: Fifty-one therapy-naïve ES-SCLC patients and ten healthy donors were enrolled. Peripheral blood mononuclear cells (PBMCs) were isolated and stained with fluorochrome-conjugated monoclonal antibodies. Multicolor flow cytometry was performed to determine the levels of CD8+ T cells and CD4+ Tregs, as well as their correlation with inflammatory indices and clinical outcomes. Results: ES-SCLC patients harbored higher percentages of CD8+ Teffs (p = 0.005) and FOXP3+ Tregs (p < 0.0001) in circulation before therapy compared with healthy donors. In addition, high levels of CD3+CD8+ T effectors were associated with longer PFS (p = 0.018) and longer OS (p = 0.012) compared with patients bearing low levels, while Tregs were not found to be predictive. More importantly, a survival benefit was observed in ES-SCLC patients with a low Treg/Teff ratio, as longer OS was observed in those with high percentages of CD8+ Teffs and low FOXP3+CTLA-4+ Tregs (p = 0.014) compared with those bearing low CD8+ Teffs and high FOXP3+CTLA-4+ Tregs. A low Treg/Teff ratio was further associated with low eosinophil levels and a low NLR before treatment initiation. Conclusions: These findings suggest a novel, easily obtainable blood-based signature that may help predict response to ICIs in ES-SCLC patients.