Pan-tumor analysis to investigate the obesity paradox in immune checkpoint blockade
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 exami...
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BMJ Publishing Group
2025-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/1/e009734.full |
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| author | Evan J Lipson Ludmila Danilova Elizabeth M Jaffee Won Jin Ho Mark Yarchoan Yasser Ged Jean Hoffman-Censits Jennifer Durham Sanjay Bansal Chester Kao Rajat Mohindra Stephanie L Alden Tanguy Y Seiwert Soren Charmsaz Howard L Li Kabeer Munjal Hua-Ling Tsai Alexei Hernandez Erin M Coyne Rachel Garonce-Hediger Laura Tang Marina Baretti Kathryn Howe G Scott Chandler Madelena Brancati Aanika Warner Ervin Griffin Mari Nakazawa Chris Thoburn Jennifer Gizzi Nicole E Gross Elsa Hallab Sarah S Shin Aditi Guha |
| author_facet | Evan J Lipson Ludmila Danilova Elizabeth M Jaffee Won Jin Ho Mark Yarchoan Yasser Ged Jean Hoffman-Censits Jennifer Durham Sanjay Bansal Chester Kao Rajat Mohindra Stephanie L Alden Tanguy Y Seiwert Soren Charmsaz Howard L Li Kabeer Munjal Hua-Ling Tsai Alexei Hernandez Erin M Coyne Rachel Garonce-Hediger Laura Tang Marina Baretti Kathryn Howe G Scott Chandler Madelena Brancati Aanika Warner Ervin Griffin Mari Nakazawa Chris Thoburn Jennifer Gizzi Nicole E Gross Elsa Hallab Sarah S Shin Aditi Guha |
| author_sort | Evan J Lipson |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8ab53f7c952740e698a3b24ac7e22152 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-8ab53f7c952740e698a3b24ac7e221522025-01-21T09:05:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-01-0113110.1136/jitc-2024-009734Pan-tumor analysis to investigate the obesity paradox in immune checkpoint blockadeEvan J Lipson0Ludmila Danilova1Elizabeth M Jaffee2Won Jin Ho3Mark Yarchoan4Yasser Ged5Jean Hoffman-Censits6Jennifer Durham7Sanjay Bansal8Chester Kao9Rajat Mohindra10Stephanie L Alden11Tanguy Y Seiwert12Soren Charmsaz13Howard L Li14Kabeer Munjal15Hua-Ling Tsai16Alexei Hernandez17Erin M Coyne18Rachel Garonce-Hediger19Laura Tang20Marina Baretti21Kathryn Howe22G Scott Chandler23Madelena Brancati24Aanika Warner25Ervin Griffin26Mari Nakazawa27Chris Thoburn28Jennifer Gizzi29Nicole E Gross30Elsa Hallab31Sarah S Shin32Aditi Guha33Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USAThe Johns Hopkins University School of Medicine, Baltimore, Maryland, USASidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USASidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USASidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USASidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USASidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USASidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USAGenentech Inc, South San Francisco, California, USASidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USAF. Hoffmann-La Roche Ltd, Basel, SwitzerlandThe Johns Hopkins University School of Medicine, Baltimore, Maryland, USASidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USASidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USAThe Johns Hopkins University School of Medicine, Baltimore, Maryland, USASidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USAThe Johns Hopkins University School of Medicine, Baltimore, Maryland, USASidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USASidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USAF. Hoffmann-La Roche Ltd, Basel, SwitzerlandGenentech Inc, South San Francisco, California, USASidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USASidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USAF. Hoffmann-La Roche Ltd, Basel, SwitzerlandSidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USAThe Johns Hopkins University School of Medicine, Baltimore, Maryland, USASidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USASidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USAThe Johns Hopkins University School of Medicine, Baltimore, Maryland, USAThe Johns Hopkins University School of Medicine, Baltimore, Maryland, USASidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USASidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USASidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USAGenentech Inc, South San Francisco, California, USABackground 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.https://jitc.bmj.com/content/13/1/e009734.full |
| spellingShingle | Evan J Lipson Ludmila Danilova Elizabeth M Jaffee Won Jin Ho Mark Yarchoan Yasser Ged Jean Hoffman-Censits Jennifer Durham Sanjay Bansal Chester Kao Rajat Mohindra Stephanie L Alden Tanguy Y Seiwert Soren Charmsaz Howard L Li Kabeer Munjal Hua-Ling Tsai Alexei Hernandez Erin M Coyne Rachel Garonce-Hediger Laura Tang Marina Baretti Kathryn Howe G Scott Chandler Madelena Brancati Aanika Warner Ervin Griffin Mari Nakazawa Chris Thoburn Jennifer Gizzi Nicole E Gross Elsa Hallab Sarah S Shin Aditi Guha Pan-tumor analysis to investigate the obesity paradox in immune checkpoint blockade Journal for ImmunoTherapy of Cancer |
| title | Pan-tumor analysis to investigate the obesity paradox in immune checkpoint blockade |
| title_full | Pan-tumor analysis to investigate the obesity paradox in immune checkpoint blockade |
| title_fullStr | Pan-tumor analysis to investigate the obesity paradox in immune checkpoint blockade |
| title_full_unstemmed | Pan-tumor analysis to investigate the obesity paradox in immune checkpoint blockade |
| title_short | Pan-tumor analysis to investigate the obesity paradox in immune checkpoint blockade |
| title_sort | pan tumor analysis to investigate the obesity paradox in immune checkpoint blockade |
| url | https://jitc.bmj.com/content/13/1/e009734.full |
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