Evaluating the impact of age on immune checkpoint therapy biomarkers.

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

doi:10.1016/j.celrep.2021.109599

Abstract

SUMMARYBoth 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.

Highlights

The association of cancer incidence with age is well established, and the phenomenon of age-related immune decline has been recognized for even longer (Gardner, 1980)
Because the immune microenvironment mediates immune checkpoint blockade (ICB) response, we focus our analysis of these large-scale data to evaluate the impact of aging on the molecular and cellular biomarkers of ICB response, such as PDL1 expression (Patel and Kurzrock, 2015), tumor mutational burden (TMB) (Yarchoan et al, 2017), (Goodman et al, 2017), cell-type composition of the immune tumor microenvironment (ITME) (Frankel et al, 2017), T cell receptor (TCR) diversity (Han et al, 2020), expression of other immune checkpoint genes (Taube, 2014), and expression of inflammation-related pathways, such as interferon gamma (Cristescu et al, 2018; Higgs et al, 2018) and transforming growth factor b (TGF-b) signaling (Tauriello et al, 2018)
In The Cancer Genome Atlas (TCGA), we identify that of these listed genes, PDL1, CD80, HAVCR2, LAG3, PDL2, and CXCL9 expression significantly increase with age (Figure 2A; p values and effect sizes are provided in Table 1), including cancer type as a covariate

Summary

SUMMARY

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 largescale 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. We observe age-related alterations that might be expected to reduce ICB efficacy, such as decreases in T cell receptor diversity 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

INTRODUCTION

RESULTS

DISCUSSION

Findings

DECLARATION OF INTERESTS

METHOD DETAILS