TY - JOUR
T1 - Pan-tumor analysis to investigate the obesity paradox in immune checkpoint blockade
AU - Alden, Stephanie L.
AU - Charmsaz, Soren
AU - Li, Howard L.
AU - Tsai, Hua Ling
AU - Danilova, Ludmila
AU - Munjal, Kabeer
AU - Brancati, Madelena
AU - Warner, Aanika
AU - Howe, Kathryn
AU - Griffin, Ervin
AU - Nakazawa, Mari
AU - Thoburn, Chris
AU - Gizzi, Jennifer
AU - Hernandez, Alexei
AU - Gross, Nicole E.
AU - Coyne, Erin M.
AU - Hallab, Elsa
AU - Shin, Sarah S.
AU - Durham, Jennifer
AU - Lipson, Evan J.
AU - Ged, Yasser
AU - Baretti, Marina
AU - Hoffman-Censits, Jean
AU - Seiwert, Tanguy Y.
AU - Guha, Aditi
AU - Bansal, Sanjay
AU - Tang, Laura
AU - Chandler, G. Scott
AU - Mohindra, Rajat
AU - Garonce-Hediger, Rachel
AU - Jaffee, Elizabeth M.
AU - Ho, Won Jin
AU - Kao, Chester
AU - Yarchoan, Mark
N1 - Publisher Copyright:
© Author(s) (or their employer(s)) 2025.
PY - 2025/1/19
Y1 - 2025/1/19
N2 - Background Obesity is a risk factor for developing cancer but is also associated with improved outcomes after treatment with immune checkpoint inhibitors (ICIs), a phenomenon called the obesity paradox. To interrogate mechanisms of divergent immune responses in obese and non-obese patients, we examined the relationship among obesity status, clinical responses, and immune profiles from a diverse, pan-tumor cohort of patients treated with ICI-based therapy. Methods From June 2021 to March 2023, we prospectively collected serial peripheral blood samples from patients with advanced or metastatic solid tumors who received ICI as standard of care at Johns Hopkins. Patients were stratified by obesity status at treatment initiation, with obesity defined as body mass index (BMI)≥30 at treatment initiation and BMI≥18.5 and <30 considered non-obese; underweight patients (BMI<18.5) were excluded. We evaluated the concentration of 37 cytokines and used cytometry by time of flight to characterize immune cell clusters and cell-surface expression markers at baseline and on-treatment. Results We enrolled 94 patients, of whom 30 (32%) were obese and 64 (68%) were non-obese. Compared with non-obese patients, obese patients had superior progression-free survival (HR: 0.44 (95% CI: 0.24 to 0.81), p=0.01) and overall survival (OS) (HR: 0.24 (95% CI: 0.07 to 0.80), p=0.02). Obese patients had lower serum IL-15 levels at treatment baseline and lower on-treatment levels of IL-6, IL-8, and IL-15. Low on-treatment IL-6 was associated with improved OS (HR: 0.27 (95% CI: 0.08 to 0.88), p=0.03), as was low on-treatment IL-8 (HR: 0.19 (95% CI: 0.05 to 0.70), p=0.01). Obese patients demonstrated lower levels of T effector cells with reduced expression of cytotoxicity markers and higher expression of exhaustion markers at baseline and on-treatment. Conclusions Obese and non-obese patients with cancer have divergent immunological responses to ICIs. Obesity is associated with reduced levels of certain inhibitory cytokines and higher expression of T-cell exhaustion markers. ICI-based therapy may more effectively reverse T-cell dysfunction in obese patients, potentially contributing to the paradoxically improved responses in this population.
AB - Background Obesity is a risk factor for developing cancer but is also associated with improved outcomes after treatment with immune checkpoint inhibitors (ICIs), a phenomenon called the obesity paradox. To interrogate mechanisms of divergent immune responses in obese and non-obese patients, we examined the relationship among obesity status, clinical responses, and immune profiles from a diverse, pan-tumor cohort of patients treated with ICI-based therapy. Methods From June 2021 to March 2023, we prospectively collected serial peripheral blood samples from patients with advanced or metastatic solid tumors who received ICI as standard of care at Johns Hopkins. Patients were stratified by obesity status at treatment initiation, with obesity defined as body mass index (BMI)≥30 at treatment initiation and BMI≥18.5 and <30 considered non-obese; underweight patients (BMI<18.5) were excluded. We evaluated the concentration of 37 cytokines and used cytometry by time of flight to characterize immune cell clusters and cell-surface expression markers at baseline and on-treatment. Results We enrolled 94 patients, of whom 30 (32%) were obese and 64 (68%) were non-obese. Compared with non-obese patients, obese patients had superior progression-free survival (HR: 0.44 (95% CI: 0.24 to 0.81), p=0.01) and overall survival (OS) (HR: 0.24 (95% CI: 0.07 to 0.80), p=0.02). Obese patients had lower serum IL-15 levels at treatment baseline and lower on-treatment levels of IL-6, IL-8, and IL-15. Low on-treatment IL-6 was associated with improved OS (HR: 0.27 (95% CI: 0.08 to 0.88), p=0.03), as was low on-treatment IL-8 (HR: 0.19 (95% CI: 0.05 to 0.70), p=0.01). Obese patients demonstrated lower levels of T effector cells with reduced expression of cytotoxicity markers and higher expression of exhaustion markers at baseline and on-treatment. Conclusions Obese and non-obese patients with cancer have divergent immunological responses to ICIs. Obesity is associated with reduced levels of certain inhibitory cytokines and higher expression of T-cell exhaustion markers. ICI-based therapy may more effectively reverse T-cell dysfunction in obese patients, potentially contributing to the paradoxically improved responses in this population.
KW - Cytokine
KW - Immune Checkpoint Inhibitor
KW - Immunotherapy
KW - Solid tumor
KW - T cell
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U2 - 10.1136/jitc-2024-009734
DO - 10.1136/jitc-2024-009734
M3 - Article
C2 - 39832896
AN - SCOPUS:85216302178
SN - 2051-1426
VL - 13
JO - Journal for immunotherapy of cancer
JF - Journal for immunotherapy of cancer
IS - 1
M1 - e009734
ER -