Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer

Immune checkpoint inhibitors (ICIs) have revolutionized advanced non-small-cell lung cancer (NSCLC) treatment, yet only a minority of patients experience lasting benefits. Identifying predictors of ICI response beyond established biomarkers like PD-L1 expression and tumor mutational burden remains crucial. Emerging research suggests the significant role of host-related factors, including psychological factors like emotional distress (ED), in cancer management and treatment response. ED, often manifested as depression and/or anxiety, is prevalent among cancer patients, with rates significantly higher than the general population. Sustained ED activates the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system, leading to the release of stress hormones (glucocorticoids, epinephrine, norepinephrine). Chronic stress impairs immune function by persistently activating these systems, potentially contributing to an immunosuppressive tumor microenvironment. Preclinical studies have demonstrated that chronic stress can impair anti-tumor immune responses and reduce the efficacy of PD-1/PD-L1 blockade. However, clinical evidence linking ED to ICI efficacy in NSCLC is limited, necessitating prospective studies. The STRESS-LUNG study, encompassing four cohorts, was designed to address this gap. This article presents findings from cohort 1 (STRESS-LUNG-1), focusing on the association between baseline ED and ICI efficacy in advanced NSCLC.

The literature extensively documents the high prevalence of emotional distress (ED), encompassing depression and anxiety, among cancer patients, significantly exceeding rates in the general population. Studies consistently link ED to poorer quality of life and prognosis in various cancers. Preclinical research strongly implicates ED in impaired antitumor immune responses through neuroendocrine mechanisms. Chronic stress activates the HPA axis and the sympathetic nervous system, leading to increased glucocorticoid release, which suppresses T cell function and inhibits antigen presentation. Animal models reveal that chronic stress promotes tumor progression and metastasis, creating an immunosuppressive tumor microenvironment. While preclinical data suggests a negative impact of ED on immunotherapy response, clinical evidence remains limited, particularly in NSCLC treated with ICIs. This study aims to fill this gap by investigating the relationship between ED and ICI efficacy in a prospective cohort of NSCLC patients.

This prospective observational study, STRESS-LUNG-1 (NCT05477979), enrolled 227 treatment-naive patients with stage IIIB-IV NSCLC receiving first-line ICI therapy (monotherapy or combination with chemotherapy) between June 2021 and July 2023. Baseline ED was assessed using the PHQ-9 (depression) and GAD-7 (anxiety) scales, with a score ≥5 in either scale defining ED. Quality of life (QoL) was measured using the EORTC QLQ-C30. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), and QoL. Exploratory analyses included ED dynamic changes during treatment and correlations between peripheral blood cortisol and ACTH levels and ICI efficacy. Statistical analyses involved Kaplan-Meier curves, log-rank tests, Cox proportional hazards regression, propensity score matching (PSM), and inverse probability of treatment weighting (IPTW) to adjust for potential confounders. The study employed rigorous statistical methods including propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) to mitigate the influence of confounding variables and enhance the reliability of the associations.

The study revealed a significant association between pretreatment ED and inferior clinical outcomes in patients with advanced NSCLC receiving ICIs. Patients with baseline ED exhibited significantly shorter median PFS (7.9 months vs. 15.5 months in the no-ED group; HR 1.73, 95% CI 1.23–2.43, P=0.002). This association remained consistent across various subgroups. The ORR was significantly lower in the ED group (46.8% vs. 62.1%; OR 0.54, P=0.022). The ED group also demonstrated a significantly lower 2-year OS rate (46.5% vs. 64.9%, P=0.016) and poorer QoL. Propensity score matching and inverse probability of treatment weighting analyses confirmed these findings. Exploratory analysis showed that the ED group had significantly higher serum cortisol levels compared to the no-ED group (P=0.019), with high cortisol levels further associated with shorter PFS (HR 1.55, P=0.014) and higher risk of death (HR 1.82, P=0.021). Analysis of ED dynamics revealed that persistent ED was associated with significantly shorter PFS (HR 1.91, P<0.001) and higher risk of OS events (HR 2.09, P=0.010) compared to patients with ED remission. Severity of ED also correlated with worse outcomes.

This study provides robust clinical evidence for the association between pretreatment ED and reduced efficacy of ICIs in advanced NSCLC. The findings support the preclinical data linking ED to impaired antitumor immune responses. The observed association between higher cortisol levels and worse survival outcomes suggests a potential neuroendocrine mechanism underlying the relationship. These findings highlight the importance of comprehensive cancer care that addresses not only the physical aspects of the disease but also the significant psychological burden experienced by patients. Interventions aimed at mitigating ED, such as psychological therapies or pharmacological approaches (e.g., β-blockers), warrant further investigation to improve ICI efficacy and patient outcomes. The consistent finding across various subgroup analyses and the use of robust statistical methods strengthen the validity of this association. The concept of 'psycho-biomarker' integration needs to be further studied.

This large prospective observational study demonstrates a significant association between pretreatment ED and reduced efficacy of ICIs in advanced NSCLC, with patients experiencing ED showing shorter PFS, lower ORR, reduced OS, and poorer QoL. Elevated cortisol levels further correlated with poorer survival outcomes. These findings emphasize the critical need for incorporating ED assessment and management into routine NSCLC care to potentially improve ICI response and patient outcomes. Further research is warranted to explore the role of ED as a predictive biomarker and to investigate the efficacy of ED-targeted interventions in this population.

This study has several limitations. It is a single-center observational study with a predominantly male, Chinese population, limiting generalizability. The OS data were not fully mature at the time of analysis. While the study demonstrates an association, it cannot establish causality. The possibility of residual confounding despite PSM and IPTW cannot be excluded. Further validation in larger, multi-center studies with diverse populations is needed. Finally, while the cutoff of PHQ-9 or GAD-7 ≥5 was efficient for this study, other cutoff scores might be relevant and need further investigation.