Nathanael R. Fillmore
Publications / 2021
paper
Cell Reports2021doi:10.1016/j.celrep.2021.109599

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, Torres Evanthia T. Roussos, Ashani Weeraratna, Hariharan Easwaran, Elana J. Fertig

Summary

Older patients often exhibit higher tumor mutational burdens and increased interferon gamma signaling, both of which are markers associated with a better response to immune checkpoint blockade therapy. These findings suggest that advanced age does not preclude a robust response to immunotherapy and support the inclusion of elderly populations in large-scale clinical trials.

Key result

Older patients exhibit increased tumor mutational burden, higher expression and decreased promoter methylation of immune checkpoint genes, and increased interferon gamma signaling, suggesting a capacity for robust response to immune checkpoint blockade.

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.

Key figure

Key figure from Evaluating the impact of age on immune checkpoint therapy biomarkers.