The immunological fitness of NSCLC patients drives the response to anti-PD1-based immunotherapy regardless of age.

BACKGROUND: Over the past decade, the number of elderly cancer patients has increased, including those with NSCLCs, most of whom are over 60 years old. NSCLC patients receive anti-PD1-based therapies. These therapies directly target the immune system by activating T cells. However, older patients exhibit several baseline immune system changes compared to their younger counterparts, which could affect treatment effectiveness. This study aims to assess the immune systems of younger (<65) and older (≥65) NSCLC patients at baseline to determine whether immune aging may alter the efficacy of immune treatments. METHODS: Seventy-eight NSCLC patients were enrolled in this study and divided into two groups on an age basis: younger (26 pts, < 65 years; young-pts) and older (52 pts, ≥65 years; old-pts). The patient’s immune profile was assessed before therapy by evaluating circulating immune cell subsets and soluble immune mediators using flow cytometry and a Luminex assay, respectively. Immune populations and soluble factors were correlated with treatment response and survival outcomes. A cohort of 27 healthy donors (HDs) served as the control group. RESULTS: Cancer patients (CPs) exhibited higher levels of CD8 (p < 0.001), Ki67 (p < 0.001), effector (p < 0.0075), and regulatory T cells (p < 0.001) than HDs. These differences remained consistent across age groups, except for effector cells, which showed a slight increase (p = 0.0932) in young-CPs compared with young-HDs. Moreover, CD3 (p < 0.001), CD4 (p < 0.001), PD1 (p < 0.001), and naïve T cells (p = 0.0144) were significantly lower in CPs than in HDs, with a similar trend across age groups, except for naïve T cells (p = 0.0748). The OS data showed no differences between the young and old groups when analyzing the entire population and the responder patients (Rs). However, young non-responders (NRs) experienced longer survival than older NRs. Multivariate analysis identified PMN (Lox1+)-MDSCs, Ki67, and response to therapy as independent predictors in NRs. The ROC curve established the cut-off for distinguishing the high-risk group, characterized by worse outcomes with elevated levels of PMN (Lox1+)-MDSCs and Ki67+ T cells, from the low-risk group (log-rank p = 0.0093). Moreover, old-NRs showed significantly higher levels of PMN (Lox1+)-MDSCs than old-Rs, and a higher percentage of CD137+PD1+ (p = 0.05) and central memory T cells (p = 0.09). CONCLUSION: The combined index of PMN(Lox1+)-MDSCs and Ki67+ T cells offers a practical tool for assessing immunological fitness in the NR setting, thereby enhancing patient stratification.