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

<b>Background</b>: 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. <b>Methods</b>: 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. <b>Results:</b> ES-SCLC patients harbored higher percentages of CD8⁺ Teffs (<i>p</i> = 0.005) and FOXP3⁺ Tregs (<i>p</i> < 0.0001) in circulation before therapy compared with healthy donors. In addition, high levels of CD3⁺CD8⁺ T effectors were associated with longer PFS (<i>p</i> = 0.018) and longer OS (<i>p</i> = 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 (<i>p</i> = 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. <b>Conclusions</b>: These findings suggest a novel, easily obtainable blood-based signature that may help predict response to ICIs in ES-SCLC patients.