Aging interacts with tumor biology to produce major changes in the immune tumor microenvironment

Abstract

1Advanced age is strongly correlated with both increased cancer incidence and general immune 2 decline. The immune tumor microenvironment (ITME) has been established as an important 3 prognostic of both therapeutic efficacy and overall patient survival. Thus, age-related immune 4 decline is an important consideration for the treatment of a large subset of cancer patients. 5Current studies of aging-related immune alterations are predominantly performed on non-6 cancerous tissue, requiring additional study into the effects of age on tumor immune infiltration. 7We leverage large scale transcriptional data sets from The Cancer Genome Atlas and the 8 Genotype-Tissue Expression project to distinguish normal age-related immune alterations from 9 age-related changes in tumor immune infiltration. We demonstrate that while there is overlap 10 between the normal immune aging phenotype and that of the ITME, there are several changes 11 in immune cell abundance that are specific to the ITME, particularly in T cell, NK cell, and 12Macrophage populations. These results suggest that aged immune cells are more susceptible to 13 tumor suppression of cytotoxic immune cell infiltration and activity than normal tissues, which 14 creates an unfavorable ITME in older patients in excess of normal immune decline with age and 15 may inform the application of existing and emerging immunotherapies for this large population 16 of patients. We additionally identify that age-related increases in tumor mutational burden are 17 associated with decreased DNA methylation and increased expression of the immune 18 checkpoint genes PDL1, CD80, and LAG3 which may have implications for therapeutic 19 application of immune checkpoint blockade in older patients. 20 21

An integrative analysis of the age-associated multi-omic landscape across cancers

“…Having identified age-related differences in the molecular landscapes of various cancers, the obvious question is: what drives these differences? Accumulating evidence has underscored the importance of tissue environment changes with ageing in cancer initiation and progression 7,8,45,54 . We reason that tissue environment changes during ageing might provide different selective advantages for tumours harbouring different molecular alterations, in turn directing tumours to different evolutionary routes.…”

“…Other probes might also have an impact on gene expression as well as might cause noise in our GSEA analysis from methylation data. Next, although we have already included tumour purity in our linear model, it is not possible to account for the different tumour-constituent cell proportions and thus fully exclude the influence of gene expression in non-cancerous cells such as infiltrating immune cells 45 . Further studies are required to provide mechanistic understanding of the impact of an ageing microenvironment in shaping tumour evolution.…”

“…15, Supplementary Data 18). Recent studies suggested alterations in immune-related gene expression and immune cell abundance changes with age in cancers [44][45][46] . In the present study, we have systematically characterised the transcriptome and methylation in relation to age across cancer types.…”