Association between pretreatment emotional distress and neoadjuvant immune checkpoint blockade response in melanoma

• Published in: Nature medicine Vol. 29; no. 12; pp. 3090 - 3099
• Main Authors: Fraterman, Itske, Reijers, Irene L. M., Dimitriadis, Petros, Broeks, Annegien, Gonzalez, M., Menzies, A. M. M., Lopez-Yurda, Marta, Kapiteijn, Ellen, van der Veldt, Astrid A. M., Suijkerbuijk, Karijn P. M., Hospers, Geke A. P., Long, Georgina V., Blank, Christian U., van de Poll-Franse, Lonneke V.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2023; Nature Publishing Group
• Subjects: 631/67/1059/2325; 631/67/1813/1634; 692/308/53/2423; 706/689/477; Antitumor activity; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cancer Research; Emotions; Gene sequencing; Glucocorticoids; Immune checkpoint inhibitors; Immune response; Infectious Diseases; Melanoma; Metabolic Diseases; Metastases; Molecular Medicine; Neurosciences; Patients; Pretreatment; Survival; γ-Interferon
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-023-02631-x

Neoadjuvant immune checkpoint blockade (ICB) outperforms adjuvant ICB for treatment of stage IIIB–D melanoma, but potential biomarkers of response, such as interferon-gamma (IFNγ) signature and tumor mutational burden (TMB), are insufficient. Preclinical studies suggest that emotional distress (ED) can negatively affect antitumor immune responses via β-adrenergic or glucocorticoid signaling. We performed a post hoc analysis evaluating the association between pretreatment ED and clinical responses after neoadjuvant ICB treatment in patients with stage IIIB–D melanoma in the phase 2 PRADO trial ( NCT02977052 ). The European Organisation for Research and Treatment of Cancer scale for emotional functioning was used to identify patients with ED ( n  = 28) versus those without ( n  = 60). Pretreatment ED was significantly associated with reduced major pathologic responses (46% versus 65%, adjusted odds ratio 0.20, P  = 0.038) after adjusting for IFNγ signature and TMB, reduced 2-year relapse-free survival (74% versus 91%, adjusted hazard ratio 3.81, P  = 0.034) and reduced 2-year distant metastasis-free survival (78% versus 95%, adjusted hazard ratio 4.33, P  = 0.040) after adjusting for IFNγ signature. RNA sequencing analyses of baseline patient samples could not identify clear β-adrenergic- or glucocorticoid-driven mechanisms associated with these reduced outcomes. Pretreatment ED may be a marker associated with clinical responses after neoadjuvant ICB in melanoma and warrants further investigation. ClinicalTrials.gov registration: NCT02977052 . In a post hoc analysis of the phase 2 PRADO trial, baseline emotional distress was associated with reduced clinical responses in patients with stage III melanoma treated with neoadjuvant ipilimumab and nivolumab.