Enhanced expression of PD-1 and other activation markers by CD4+ T cells of young but not old patients with metastatic melanoma

Brom, Rob R. H. van den; Geest, Kornelis S M van der; Brouwer, Elisabeth; Hospers, Geke A.P.; Boots, A.

doi:10.1007/s00262-018-2148-6

Cited by 7 publications

(6 citation statements)

References 31 publications

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“…The observed effects of age on the non-suppressive Tregs (fraction 3) and the conventional memory CD25 dim CD4+ T cells (fraction 4) can be attributed solely to the decrease in PD-1 + CD4+ memory T-cell frequencies in older females. Previously, we reported on higher frequencies of PD-1-expressing CD4+ T cells in young, but not old patients with metastatic melanoma, data consistent with the current finding albeit that effects of sex were not documented [ 23 ].…”

Section: Discussionsupporting

confidence: 92%

Effect of age and sex on immune checkpoint expression and kinetics in human T cells

et al. 2020

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Background Immune checkpoints are crucial molecules in maintaining a proper immune balance. Even though age and sex are known to have effects on the immune system, the interplay between age, sex and immune checkpoint expression by T cells is not known. The aim of this study was to determine whether age and sex affect immune checkpoint expression by T cells and if age and sex affect the kinetics of immune checkpoint expression following ex vivo stimulation. In this study, whole blood samples of 20 healthy young adults (YA, 9 males and 11 females) and 20 healthy older adults (OA, 9 males and 11 females) were stained for lymphocyte lineage markers and immune checkpoints and frequencies of CD28+, PD-1+, VISTA+ and CD40L+ T cells were determined. Immune checkpoint expression kinetics were studied following ex vivo anti-CD3/anti-CD28 stimulation of T cells from young and older healthy adults. Results We report an age-associated increase of CD40L + CD4+ and CD40L + CD8+ T-cell frequencies, whereas CD40+ B-cell frequencies were decreased in older adults, suggesting modulation of the CD40L-CD40 interaction with age. Immune checkpoint expression kinetics revealed differences in magnitude between CD4+ and CD8+ T cells independent of age and sex. Further analysis of CD4+ T-cell subsets revealed an age-associated decrease of especially PD-1 + CD4+ memory T cells which tracked with the female sex. Conclusion Collectively, our results demonstrate that both age and sex modulate expression of immune checkpoints by human T cells. These findings may have implications for optimising vaccination and immune checkpoint immunotherapy and move the field towards precision medicine in the management of older patient groups.

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Section: Discussionsupporting

confidence: 92%

Effect of age and sex on immune checkpoint expression and kinetics in human T cells

et al. 2020

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“…Notably, in this current study, we did not observe differences in expression of CTLA-4 or PD-1 between younger and older memory PB CD4 T cells (albeit from unmatched donor blood samples), potentially highlighting a gut-specific effect. Although previous studies have noted an age-associated increase in CTLA-4 or PD-1 expression on blood CD4 T cells [ 26 – 29 ], the lack of an apparent age effect observed here is in agreement with a number of other studies [ 30 – 33 ] and may relate to study populations (e.g. age range, sex) and/or the type of CD4 T cell evaluated (e.g.…”

Section: Discussionsupporting

confidence: 92%

Reduced immune-regulatory molecule expression on human colonic memory CD4 T cells in older adults

et al. 2021

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Background The etiology of the low-level chronic inflammatory state associated with aging is likely multifactorial, but a number of animal and human studies have implicated a functional decline of the gastrointestinal immune system as a potential driver. Gut tissue-resident memory T cells play critical roles in mediating protective immunity and in maintaining gut homeostasis, yet few studies have investigated the effect of aging on human gut T cell immunity. To determine if aging impacted CD4 T cell immunity in the human large intestine, we utilized multi-color flow cytometry to measure colonic lamina propria (LP) CD4 T cell frequencies and immune-modulatory marker expression in younger (mean ± SEM: 38 ± 1.5 yrs) and older (77 ± 1.6 yrs) adults. To determine cellular specificity, we evaluated colon LP CD8 T cell frequency and phenotype in the same donors. To probe tissue specificity, we evaluated the same panel of markers in peripheral blood (PB) CD4 T cells in a separate cohort of similarly aged persons. Results Frequencies of colonic CD4 T cells as a fraction of total LP mononuclear cells were higher in older persons whereas absolute numbers of colonic LP CD4 T cells per gram of tissue were similar in both age groups. LP CD4 T cells from older versus younger persons exhibited reduced CTLA-4, PD-1 and Ki67 expression. Levels of Bcl-2, CD57, CD25 and percentages of activated CD38+HLA-DR+ CD4 T cells were similar in both age groups. In memory PB CD4 T cells, older age was only associated with increased CD57 expression. Significant age effects for LP CD8 T cells were only observed for CTLA-4 expression, with lower levels of expression observed on cells from older adults. Conclusions Greater age was associated with reduced expression of the co-inhibitory receptors CTLA-4 and PD-1 on LP CD4 T cells. Colonic LP CD8 T cells from older persons also displayed reduced CTLA-4 expression. These age-associated profiles were not observed in older PB memory CD4 T cells. The decline in co-inhibitory receptor expression on colonic LP T cells may contribute to local and systemic inflammation via a reduced ability to limit ongoing T cell responses to enteric microbial challenge.

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“…The naïve T-cell compartment declines 2-5-fold between the ages of 30 and 70 years old, and the ability to establish immunological memory to newly introduced antigens is compromised [28,29]. Furthermore, it was shown that CD4+ T-cells of patients ≤ 50 show more signs of activation, when compared to patients ≥ 65 years of age [30]. These factors can contribute to a less effective T-cell immune response against melanoma cells after immunotherapy with checkpoint inhibition in older adults and elderly as compared to the younger population.…”

Section: Discussionmentioning

confidence: 99%

Age Does Matter in Adolescents and Young Adults versus Older Adults with Advanced Melanoma; A National Cohort Study Comparing Tumor Characteristics, Treatment Pattern, Toxicity and Response

Kooij

Wetzels

Aarts

et al. 2020

Cancers

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Cutaneous melanoma is a common type of cancer in Adolescents and Young Adults (AYAs, 15–39 years of age). However, AYAs are underrepresented in clinical trials investigating new therapies and the outcomes from these therapies for AYAs are therefore unclear. Using prospectively collected nation-wide data from the Dutch Melanoma Treatment Registry (DMTR), we compared baseline characteristics, mutational profiles, treatment strategies, grade 3–4 adverse events (AEs), responses and outcomes in AYAs (n = 210) and older adults (n = 3775) who were diagnosed with advanced melanoma between July 2013 and July 2018. Compared to older adults, AYAs were more frequently female (51% versus 40%, p = 0.001), and had a better Eastern Cooperative Oncology Group performance status (ECOG 0 in 54% versus 45%, p = 0.004). BRAF and NRAS mutations were age dependent, with more BRAF V600 mutations in AYAs (68% versus 46%) and more NRAS mutations in older adults (13% versus 21%), p < 0.001. This finding translated in distinct first-line treatment patterns, where AYAs received more initial targeted therapy. Overall, grade 3–4 AE percentages following first-line systemic treatment were similar for AYAs and older adults; anti-PD-1 (7% versus 14%, p = 0.25), anti-CTLA-4 (16% versus 33%, p = 0.12), anti-PD-1 + anti-CTLA-4 (67% versus 56%, p = 0.34) and BRAF/MEK-inhibition (14% versus 23%, p = 0.06). Following anti-CTLA-4 treatment, no AYAs experienced a grade 3–4 colitis, while 17% of the older adults did (p = 0.046). There was no difference in response to treatment between AYAs and older adults. The longer overall survival observed in AYAs (hazard ratio (HR) 0.7; 95% CI 0.6–0.8) was explained by the increased cumulative incidence of non-melanoma related deaths in older adults (sub-distribution HR 2.8; 95% CI 1.5–4.9), calculated by competing risk analysis. The results of our national cohort study show that baseline characteristics and mutational profiles differ between AYAs and older adults with advanced melanoma, leading to different treatment choices made in daily practice. Once treatment is initiated, AYAs and older adults show similar tumor responses and melanoma-specific survival.

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Enhanced expression of PD-1 and other activation markers by CD4+ T cells of young but not old patients with metastatic melanoma

Cited by 7 publications

References 31 publications

Effect of age and sex on immune checkpoint expression and kinetics in human T cells

Effect of age and sex on immune checkpoint expression and kinetics in human T cells

Reduced immune-regulatory molecule expression on human colonic memory CD4 T cells in older adults

Age Does Matter in Adolescents and Young Adults versus Older Adults with Advanced Melanoma; A National Cohort Study Comparing Tumor Characteristics, Treatment Pattern, Toxicity and Response

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