Differences in TCR-Vβ Repertoire and Effector Phenotype between Tumor Infiltrating Lymphocytes and Peripheral Blood Lymphocytes Increase with Age

Shao, Hongwei; Ou, Yusheng; Wang, Teng; Shen, Han; Wu, Fenglin; Zhang, Wenfeng; Tao, Changli; Yin, Yuan; Bo, Huaben; Wang, Hui; Huang, Shulin

doi:10.1371/journal.pone.0102327

Cited by 15 publications

(8 citation statements)

References 43 publications

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“…On this basis, further investigations were necessary to fully understand the association between DNA cumulative damage and frailty status. Therefore, in the present study, we addressed the possible relationship between frailty status and different genomic outcomes, chosen on the basis of their demonstrated link to aging or age-related diseases (16,33), in a population of frail, prefrail, and nonfrail older adults.…”

Section: Discussionmentioning

confidence: 99%

Exploring Genetic Outcomes as Frailty Biomarkers

Valdiglesias

Sánchez-Flores

Marcos-Pérez

et al. 2018

The Journals of Gerontology: Series A

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Frailty has emerged as a reliable measure of the aging process. Since the early detection of frailty is crucial to prevent or even revert it, the use of biomarkers would allow an earlier and more objective identification of frail individuals. In order to improve the understanding of the biological features associated with frailty as well as to explore different biomarkers for its early identification, several genetic outcomes - mutagenicity, different types of genetic damage, and cellular repair capacity - were analysed in a population of older adults classified into frail, pre-frail and non-frail. Besides, influence of clinical parameters - nutritional status and cognitive status - was evaluated. No association of mutation rate or primary DNA damage with frailty was observed. However, DNA repair capacity showed a non-significant tendency to decrease with frailty, and persistent levels of phosphorylated H2AX, as indicative of DNA breakage, increased progressively with frailty severity. These results support the possible use of H2AX phosphorylation to provide information regarding frailty severity. Further investigation is necessary to determine the consistency of the current findings in different populations and larger sample sizes, to eventually standardize biomarkers to be used in clinics, and to fully understand the influence of cognitive impairment.

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Section: Discussionmentioning

confidence: 99%

Exploring Genetic Outcomes as Frailty Biomarkers

Valdiglesias

Sánchez-Flores

Marcos-Pérez

et al. 2018

The Journals of Gerontology: Series A

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“…This may lead to a decrease in the release of neo-antigens, thus impairing the initiation of antitumor immune responses [ 22 ]. Notably, CD8+ T cells were the major mediator influenced by the PD-1 ligand pathway, and aging is associated with a decreased compartment of naïve CD8+ T cells [ 23 ]. This preclinical finding, in the context of cancer, may partly account for our clinical results.…”

Section: Discussionmentioning

confidence: 99%

The effectiveness of PD-1 inhibitors in non-small cell lung cancer (NSCLC) patients of different ages

Qian

et al. 2017

Oncotarget

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BackgroundImmunosenescence, the age-related decline of immunity, affects the immune responses of non-small cell lung cancer (NSCLC) patients. Through immune responses, programmed death-1 (PD-1) inhibitors exert their antitumor robustness. In different ages of NSCLC patients, especially the older patients, the effectiveness of PD-1 inhibitors remains unclear. It is still controversial whether pembrolizumab or nivolumab should be used in treating NSCLC patients.Results2,192 NSCLC patients from four phase III RCTs were included. PD-1 inhibitors significantly prolonged the OS in both younger group (<65-year-age) (HR: 0.64, 95% CI: 0.54–0.75, P = 0.000) and older group (≥65-year-age) (HR: 0.68, 95% CI: 0.54–0.81, P = 0.001) than chemotherapy. Among patients aged over 75, no significantly longer OS was observed (HR: 1.02, 95% CI: 0.35–1.69, P = 0.971) than controls. In the older group (≥65-year-age), HR of OS favors nivolumab rather than pembrolizumab.ConclusionsAmong patients aged over 75, no significantly prolonged overall survival was observed compared with chemotherapy. In comparison with pembrolizumab, nivolumab was associated with better OS in older NSCLC patients (≥65-year-age), and better PFS in all NSCLC patients. Older patients, especially those aged over 75, should be paid more attention to in the future clinical trials, guidelines, and clinical practice.MethodsThe authors included clinical trials testing PD-1 inhibitors (nivolumab and pembrolizumab) compared with chemotherapies in older and younger patients. The authors used the hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS) and progression-free survival (PFS).

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“…Furthermore, often, responses against self-antigens (23,26) were investigated, whereas actually neoantigens are thought to be the main mediators of tumor rejection (32). Such approaches are valuable for translational research on TCR candidates targeting human tumor antigens but are limited in reflecting natural antitumor T cell immunity because endogenous antigen-specific T cell populations develop from small numbers of precursors (33)(34)(35) and are polyclonal (36)(37)(38). Tracking TCR avidity-dependent T cell fate over space and time is therefore challenging, which makes surrogate markers for TCR avidity particularly relevant.…”

Section: Introductionmentioning

confidence: 99%

Signatures of recent activation identify a circulating T cell compartment containing tumor-specific antigen receptors with high avidity

et al. 2022

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T cell receptor (TCR) avidity is assumed to be a major determinant of the spatiotemporal fate and protective capacity of tumor-specific T cells. However, monitoring polyclonal T cell responses with known TCR avidities in vivo over space and time remains challenging. Here, we investigated the fate and functionality of tumor neoantigen–specific T cells with TCRs of distinct avidities in a well-established, reductionist preclinical tumor model and human patients with melanoma. To this end, we used polyclonal T cell transfers with in-depth characterized TCRs together with flow cytometric phenotyping in mice inoculated with MC38 OVA tumors. Transfer of T cells from retrogenic mice harboring TCRs with high avidity resulted in best tumor protection. Unexpectedly, we found that both high- and low-avidity T cells are similarly abundant within the tumor and adopt concordant phenotypic signs of exhaustion. Outside the tumor, high-avidity TCR T cells were not generally overrepresented but, instead, selectively enriched in T cell populations with intermediate PD-1 protein expression. Single-cell sequencing of neoantigen-specific T cells from two patients with melanoma—combined with transgenic reexpression of identified TCRs by CRISPR-Cas9–mediated orthotopic TCR replacement—revealed high-functionality TCRs to be enriched in T cells with RNA signatures of recent activation. Furthermore, of 130 surface protein candidates, PD-1 surface expression was most consistently enriched in functional TCRs. Together, our findings show that tumor-reactive TCRs with high protective capacity circulating in peripheral blood are characterized by a signature of recent activation.

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Differences in TCR-Vβ Repertoire and Effector Phenotype between Tumor Infiltrating Lymphocytes and Peripheral Blood Lymphocytes Increase with Age

Cited by 15 publications

References 43 publications

Exploring Genetic Outcomes as Frailty Biomarkers

Exploring Genetic Outcomes as Frailty Biomarkers

The effectiveness of PD-1 inhibitors in non-small cell lung cancer (NSCLC) patients of different ages

Signatures of recent activation identify a circulating T cell compartment containing tumor-specific antigen receptors with high avidity

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