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Simple Summary: The development of immune checkpoint inhibitors has revolutionized the treatment of lung cancer by becoming the standard therapy for advanced non-small cell lung cancer that lacks specific genetic mutations. However, not all patients respond equally, underscoring the need for biomarkers to predict treatment response. To address this, a study was conducted with 55 lung cancer patients treated with immune checkpoint inhibitors to investigate whether biomarkers like TCRβ diversity and certain cytokines linked to T cell activity could predict the response to immunotherapy. While higher TCRβ clonality and specific cytokine levels appeared to be associated with improved survival rates, the findings were not statistically significant. Specifically, higher levels of IL-2 and IL-15 were linked to shorter overall survival, with high IL-15 levels increasing the risk of death threefold in multivariable analysis. Although further research with larger sample sizes is needed for confirmation, these results offer promising insights into potential markers for predicting responses to immune checkpoint inhibitors. The development of immune checkpoint inhibitors (ICIs) has changed the therapeutic paradigm of lung cancer (LC), becoming the standard of treatment for previously untreated advanced non-small cell lung cancer (NSCLC) without actionable mutations. It has allowed the achievement of durable responses and resulted in significant survival benefits. However, not all patients respond; hence, molecular biomarkers are needed to help us predict which patients will respond. With this objective, a prospective observational study was designed, including a cohort of 55 patients with NSCLC who received ICIs. We studied whether biomarkers such as TCRβ and specific cytokines involved in the regulation of T cell activity were related to the immunotherapy response. In the survival analysis, it was found that patients with higher TCRβ clonality, lower TCRβ evenness, higher TCRβ Shannon diversity and lower TCRβ convergence had higher overall survival (OS) and progression-free survival (PFS). However, no statistically significant association was observed. Regarding cytokines, those patients with higher levels of IL-2 and IL-15 presented statistically significantly shorter OS and PFS, respectively. In fact, in the multivariable analysis, the high IL-15 level increased the risk of death by three times. Although the sample size was small and more studies are needed to confirm our results, our study reveals promising markers of responses to ICIs. [ABSTRACT FROM AUTHOR]

Simple Summary: In recent years, studies in cancer immunotherapy have focused on finding predictive response biomarkers to anticipate which patients will respond to each kind of treatment, optimizing treatment strategy and reducing toxicities and costs. Unfortunately, these studies are still limited, and no conclusive results have been obtained. This study was designed to prospectively analyze a cohort of lung cancer patients receiving immunotherapy attempting to determine cellular biomarkers of response, as T-lymphocyte and natural killer (NK) cell subsets, in peripheral blood. Despite previous studies, none of these populations have been identified yet with clinical relevance to be established in clinical practice. In our study, we have identified a subset of circulating CD56+CD16-PD-1+ NK cells showing a good predictive ability. These results contribute to the development of precision medicine protocols where we could stratify patients according to the expected treatment response to choose the best option for each patient. (1) Despite the effectiveness of immune checkpoint inhibitors (ICIs) in lung cancer, there is a lack of knowledge about predictive biomarkers. The objective of our study is to analyze different subsets of T-lymphocytes and natural killer (NK) cells as predictive biomarkers in a cohort of patients with nonsmall cell lung cancer (NSCLC) treated with ICI. (2) This is an observational, prospective study with 55 NSCLC patients treated with ICI. A total of 43 T and NK cell subsets are analyzed in peripheral blood, including the main markers of exhaustion, differentiation, memory, activation, and inhibition. (3) Regarding the descriptive data, Granzyme B+CD4+ Treg lymphocytes stand out (median 17.4%), and within the NK populations, most patients presented cytotoxic NK cells (CD56+CD3−CD16+GranzymeB+; median 94.8%), and about half of them have highly differentiated adaptive-like NK cells (CD56+CD3−CD16+CD57+ (mean 59.8%). A statistically significant difference was observed between the expression of PD1 within the CD56bright NK cell subpopulation (CD56+CD3−CD16−PD-1+) (p = 0.047) and a better OS. (4) Circulating immune cell subpopulations are promising prognostic biomarkers for ICI. Pending on validation with a larger sample, here we provide an analysis of the major circulating T and NK cell subsets involved in cancer immunity, with promising results despite a small sample size. [ABSTRACT FROM AUTHOR]