Comprehensive transcriptome profiling in elderly cancer patients reveals aging‐altered immune cells and immune checkpoints

Abstract

Aging is the single most significant risk factor for cancer development. However, the potential impact of aging on cancer microenvironment remains poorly understood. Here, we performed a pan-cancer transcriptome analysis to identify aging-specific molecular patterns across 18 cancer types. Strikingly, aging-specific molecular features define human cancers into two types, including the strong and weak aging-effect groups. Significant aging associated molecular signature was observed in 16 cancer types (strong aging-effect group) such as breast invasive carcinoma and acute myeloid leukemia. In such 16 cancer types, old patients showed obvious poor survival compared to young patients, but this observation was not found in the weak aging-effect cancers. Aging-associated cancer-relevant molecules significantly enriched in 23 pathways including EMT and KRAS signaling. More interestingly, in cancer microenvironment, aging significantly restrains adaptive immunity, but strikingly, increases the number of infiltrated innate immune cells. Further analysis shows that the expression of immune checkpoints including PD-1, PD-L1, PD-L2, and CTLA-4 are mostly correlated with age. In general, cancer cells in elderly patients show a more aggressive phenotype and their surrounding microenvironment is under a more immune suppression status compared with young patients. Our study provides a systematic understanding of aging-associated molecular features in pan-cancer and indicates a clinical requirement to develop aging-specific therapeutic strategies in a majority of cancer types. Furthermore, aging-altered immune cells and immune checkpoints should be considered in cancer immunotherapy. This article is protected by copyright. All rights reserved.

Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity

“…Based on its mode of action involving core machineries (SIRT1 and AMPK) causally involved in the hallmarks of aging, such as epigenetic alterations, deregulated nutrient sensing, or mitochondrial dysfunction [62,95], RSV has classically been considered an archetype member of the downstream type of calorie restriction mimetics (CRMs) including rapamycin, metformin, and polyamines (spermidine). Intriguingly, because normal human aging is characterized by a progressive decline in immune surveillance that is accompanied by PD-L1 upregulation to favor cancer initiation and progression even in the absence of a more complex mutational landscape [96][97][98][99][100], the suppression of PD-L1 signaling via direct targeting of PD-L1 glycosylation enzymes could represent a new immunometabolic mechanism through which RSV might prevent immune dysfunction and cancer development in the context of aging. Although there are conflicting data about whether the SIRT1 agonist activity of RSV might alleviate glucose intolerance in humans, it is reasonable to suggest that the ability of RSV to mimic acarbose in enhancing anticancer T-cell immunity [101,102] uncovers an immunologic dimension to the previously observed capacity of RSV to exert anti-diabetic effects via direct inhibition of GAA [51][52][53][54][103][104][105].…”

Alterations in Immune-Related Genes as Potential Marker of Prognosis in Breast Cancer

“…This low intensity and chronic inflammatory microenvironment promoted tumorigenesis and progression. In elderly patients, proliferation and activity of CD4+ and CD8+ T cells and B cells decreased, while those of immunosuppressive cells increased (53), which formed an immunosuppressive microenvironment that facilitated tumor progression (16). However, few prospective clinical trials have focused on the elderly, and limited studies have demonstrated that older patients benefit from chemotherapy as well as targeted therapies but exhibit more severe cardiotoxicity and bone marrow disorders (54).…”

An Integrative Analysis of the Age-Associated Genomic, Transcriptomic and Epigenetic Landscape across Cancers

“…11, Supplementary Table 16). Previous studies suggested alterations in immune-related gene expression and immune cell abundance changes with age in cancers 38,39 . In the present study, we have systematically characterised the transcriptome and methylation in relation to age across cancer types.…”