Age-related divergence of circulating immune responses in patients with solid tumors treated with immune checkpoint inhibitors

Chester Kao, Soren Charmsaz, Hua-Ling Tsai, Khaled Aziz, Daniel H. Shu, Kabeer Munjal, Ervin Griffin, James M. Leatherman, Evan J. Lipson, Yasser Ged, Jeannie Hoffman-Censits, Howard L. Li, Elsa Hallab, Madelena Brancati, Mari Nakazawa, Stephanie Alden, Christopher Thoburn, Nicole E. Gross, Alexei G. Hernandez, Erin M. Coyne, Emma Kartalia, Marina Baretti, Elizabeth M. Jaffee, Sanjay Bansal, Laura Tang, G. Scott Chandler, Rajat Mohindra, Won Jin Ho (), Mark Yarchoan () and Daniel J. Zabransky ()
Additional contact information
Chester Kao: Johns Hopkins University School of Medicine
Soren Charmsaz: Johns Hopkins University School of Medicine
Hua-Ling Tsai: Johns Hopkins University School of Medicine
Khaled Aziz: Johns Hopkins University School of Medicine
Daniel H. Shu: Johns Hopkins University School of Medicine
Kabeer Munjal: Johns Hopkins University School of Medicine
Ervin Griffin: Johns Hopkins University School of Medicine
James M. Leatherman: Johns Hopkins University School of Medicine
Evan J. Lipson: Johns Hopkins University School of Medicine
Yasser Ged: Johns Hopkins University School of Medicine
Jeannie Hoffman-Censits: Johns Hopkins University School of Medicine
Howard L. Li: Johns Hopkins University School of Medicine
Elsa Hallab: Johns Hopkins University School of Medicine
Madelena Brancati: Johns Hopkins University School of Medicine
Mari Nakazawa: Johns Hopkins University School of Medicine
Stephanie Alden: Johns Hopkins University School of Medicine
Christopher Thoburn: Johns Hopkins University School of Medicine
Nicole E. Gross: Johns Hopkins University School of Medicine
Alexei G. Hernandez: Johns Hopkins University School of Medicine
Erin M. Coyne: Johns Hopkins University School of Medicine
Emma Kartalia: Johns Hopkins University School of Medicine
Marina Baretti: Johns Hopkins University School of Medicine
Elizabeth M. Jaffee: Johns Hopkins University School of Medicine
Sanjay Bansal: South San Francisco
Laura Tang: South San Francisco
G. Scott Chandler: F. Hoffmann-La Roche Ltd
Rajat Mohindra: F. Hoffmann-La Roche Ltd
Won Jin Ho: Johns Hopkins University School of Medicine
Mark Yarchoan: Johns Hopkins University School of Medicine
Daniel J. Zabransky: Johns Hopkins University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Most new cancer diagnoses occur in patients over the age of 65. The composition and function of the immune system changes with age, but how the aged immune system affects responses to immune checkpoint inhibitor (ICI) cancer therapies remains incompletely understood. Here, using multiplex cytokine assay and high-parameter mass cytometry, we analyze prospectively collected blood samples from 104 cancer patients receiving ICIs. We find aged patients ( ≥ 65-years-old; n = 54) derive similar clinical outcomes as younger patients (n = 50). However, aged, compared to young, patients have divergent immune phenotypes at baseline that persist during ICI therapy, including diminished cytokine responses, reduced pools of naïve T cells with increased relative expression of immune checkpoint molecules, and more robust effector T cell expansion in responders compared to non-responders. Our study provides insights into age-stratified mechanisms of ICI effects while also implying the utility of age-tailored immunotherapeutic approaches.

Date: 2025
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DOI: 10.1038/s41467-025-58512-z

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