CD137+ and regulatory T cells as independent prognostic factors of survival in advanced non-oncogene addicted NSCLC patients treated with immunotherapy as first-line

Background: Immune checkpoint inhibitors (ICIs), administered alone or combined with chemotherapy, are the standard of care in advanced non-oncogene addicted Non-Small Cell Lung Cancer (NSCLC). Despite these treatments' success, most long-term survival benefit is restricted to approximately 20% of patients, highlighting the need to identify novel biomarkers to optimize treatment strategies. In several solid tumors, immune soluble factors, the activatory CD137+Tcells, and the immunosuppressive cell subsets Tregs and MDSCs (PMN(Lox1+)-MDSC and M-MDSCs) correlated with responses to ICIs and clinical outcomes thus becoming appealing predictive and prognostic factors. This study investigated the role of distinct CD137+Tcell subsets, Tregs, MDSCs, and immune-soluble factors in NSCLC patients as possible biomarkers. Methods: The levels of Tcells, MDSCs and soluble factors were evaluated in 89 metastatic NSCLC patients who underwent ICIs as first- or second-line treatment. Tcell analysis was performed by cytoflurimetry evaluating Tregs and different CD137+Tcell subsets also combined with CD3+, CD8+, PD1+, and Ki67+markers. Circulating cytokines and immune checkpoints were also evaluated by Luminex analysis. All these parameters were correlated with several clinical factors (age, sex, smoking status, PS and TPS), response to therapy, OS, and PFS. The analyses were conducted in the overall population and in patients treated with ICIs as first-line (naïve patients). Results: In both groups of patients, high levels of circulating CD137+ and CD137+PD1+T cells (total, CD4 and CD8) and the soluble factor LAG3 positively correlated with response to therapy. In naïve patients, PMN(Lox1+)-MDSCs negatively correlated with clinical response, and a high percentage of Treg was associated with favorable survival. Moreover, the balance between Treg/CD137+Tcells or PMN(Lox1+)-MDSC/CD137+Tcells was higher in non-responding patients and was associated with poor survival. CD137+Tcells and Tregs resulted as two positive independent prognostic factors. Conclusion: High levels of CD137+, CD137+PD1+Tcells and sLAG3 could predict the response to ICIs in NSCLC patients independently by previous therapy. Combining the evaluation of CD137+Tcells and Treg also as Treg/CD137+Tcells ratio it is possible to identify patients with longer survival in naïve patients.