Pan-tumor analysis to investigate the obesity paradox in immune checkpoint blockade

• DOI: 10.1136/jitc-2024-009734
• Publication Date: 2025-01-20T06:15:54Z
• Authors: Stephanie L Alden; Soren Charmsaz; Howard L Li; Hua-Ling Tsai; Ludmila Danilova; Kabeer Munjal; Madelena Brancati; Aanika Warner; Kathryn Howe; Ervin Griffin; Mari Nakazawa; Chris Thoburn; Jennifer Gizzi; Alexei Hernandez; Nicole E Gross; Erin M Coyne; Elsa Hallab; Sarah S Shin; Jennifer Durham; Evan J Lipson; Yasser Ged; Marina Baretti; Jean Hoffman-Censits; Tanguy Y Seiwert; Aditi Guha; Sanjay Bansal; Laura Tang; G Scott Chandler; Rajat Mohindra; Rachel Garonce-He...; Elizabeth M Jaffee; Won Jin Ho; Chester Kao; Mark Yarchoan
• Keywords: Underweight; Obesity paradox; Immune checkpoint

Background Obesity is a risk factor for developing cancer but also associated with improved outcomes after treatment immune checkpoint inhibitors (ICIs), phenomenon called the obesity paradox. To interrogate mechanisms of divergent responses in obese and non-obese patients, we examined relationship among status, clinical responses, profiles from diverse, pan-tumor cohort patients treated ICI-based therapy. Methods From June 2021 to March 2023, prospectively collected serial peripheral blood samples advanced or metastatic solid tumors who received ICI as standard care at Johns Hopkins. Patients were stratified by status initiation, defined body mass index (BMI)≥30 initiation BMI≥18.5 <30 considered non-obese; underweight (BMI<18.5) excluded. We evaluated concentration 37 cytokines used cytometry time flight characterize cell clusters cell-surface expression markers baseline on-treatment. Results enrolled 94 whom 30 (32%) 64 (68%) non-obese. Compared had superior progression-free survival (HR: 0.44 (95% CI: 0.24 0.81), p=0.01) overall (OS) 0.07 0.80), p=0.02). Obese lower serum IL-15 levels on-treatment IL-6, IL-8, IL-15. Low IL-6 was OS 0.27 0.08 0.88), p=0.03), low IL-8 0.19 0.05 0.70), p=0.01). demonstrated T effector cells reduced cytotoxicity higher exhaustion Conclusions have immunological ICIs. certain inhibitory T-cell markers. therapy may more effectively reverse dysfunction potentially contributing paradoxically this population.