Evaluating the impact of age on immune checkpoint therapy biomarkers

Rossin Erbe; Zheyu Wang; Sharon Wu; Joanne Xiu; Neeha Zaidi; Jennifer La; David Tuck; Nathanael Fillmore; Nicolas A Giraldo; Michael Topper; Stephen Baylin; Marc Lippman; Claudine Isaacs; Reva Basho; Ilya Serebriiskii; Heinz-Josef Lenz; Igor Astsaturov; John Marshall; Josephine Taverna; Jerry Lee; Elizabeth M Jaffee; Evanthia T Roussos Torres; Ashani Weeraratna; Hariharan Easwaran; Elana J Fertig

doi:10.1016/j.celrep.2021.109599

Evaluating the impact of age on immune checkpoint therapy biomarkers

Cell Rep. 2021 Aug 24;36(8):109599. doi: 10.1016/j.celrep.2021.109599.

Authors

Rossin Erbe¹, Zheyu Wang², Sharon Wu³, Joanne Xiu³, Neeha Zaidi⁴, Jennifer La⁵, David Tuck⁵, Nathanael Fillmore⁵, Nicolas A Giraldo⁶, Michael Topper⁴, Stephen Baylin⁴, Marc Lippman⁷, Claudine Isaacs⁷, Reva Basho⁸, Ilya Serebriiskii⁹, Heinz-Josef Lenz¹⁰, Igor Astsaturov⁹, John Marshall⁷, Josephine Taverna¹¹, Jerry Lee¹⁰, Elizabeth M Jaffee⁴, Evanthia T Roussos Torres¹⁰, Ashani Weeraratna¹², Hariharan Easwaran⁴, Elana J Fertig¹³

Affiliations

¹ McKusick-Nathans Institute of the Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
² Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
³ Caris Life Sciences, Irving, TX, USA.
⁴ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁵ VA Boston Healthcare System, Boston, MA, USA.
⁶ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁷ Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
⁸ Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute, 8700 Beverly Boulevard, #AC-1046A, Los Angeles, CA 90048, USA.
⁹ Fox Chase Cancer Center, Philadelphia, PA, USA.
¹⁰ Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹¹ Division of Hematology and Oncology, Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
¹² Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹³ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Applied Mathematics and Statistics, Johns Hopkins University Whiting School of Engineering, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins Bloomberg School of Medicine, Baltimore, MD, USA. Electronic address: ejfertig@jhmi.edu.

Abstract

Both tumors and aging alter the immune landscape of tissues. These interactions may play an important role in tumor progression among elderly patients and may suggest considerations for patient care. We leverage large-scale genomic and clinical databases to perform comprehensive comparative analysis of molecular and cellular markers of immune checkpoint blockade (ICB) response with patient age. These analyses demonstrate that aging is associated with increased tumor mutational burden, increased expression and decreased promoter methylation of immune checkpoint genes, and increased interferon gamma signaling in older patients in many cancer types studied, all of which are expected to promote ICB efficacy. Concurrently, we observe age-related alterations that might be expected to reduce ICB efficacy, such as decreases in T cell receptor diversity. Altogether, these changes suggest the capacity for robust ICB response in many older patients, which may warrant large-scale prospective study on ICB therapies among patients of advanced age.

Keywords: TCGA; aging; cancer; genomics; immune; immunotherapy.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Age Factors*
B7-H1 Antigen / genetics
B7-H1 Antigen / immunology*
Biomarkers, Tumor / genetics*
Biomarkers, Tumor / isolation & purification*
Genomics
Humans
Immunotherapy / methods
Neoplasms / drug therapy*
Neoplasms / genetics
Prospective Studies

Substances

B7-H1 Antigen
Biomarkers, Tumor

Abstract

Publication types

MeSH terms

Substances

Grants and funding