Immunosenescence profile and expression of the aging biomarker (p16INK4a) in testicular cancer survivors treated with chemotherapy

Bourlon, María Teresa; Velazquez, Hugo E; Hinojosa, Juan; Orozco, Luis; Rios-Corzo, Ricardo; Lima, Guadalupe; Llórente, Luis; Hernández‐Ramírez, Diego F.; Valentin-Cortez, Francisco J; Medina-Rangel, Irene; Atisha‐Fregoso, Yemil

doi:10.1186/s12885-020-07383-2

Cited by 13 publications

(9 citation statements)

References 20 publications

(27 reference statements)

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“…Overexpression of PDHA1 increases reactive oxygen species (ROS) production, mitochondrial respiration, and apoptosis ( Wang et al, 2022 ), which may be a driver of the disturbance of the testicular immune microenvironment. Increased expression of CDKN2A correlates with a lymphocyte phenotype associated with immunosenescence ( Bourlon et al, 2020 ). Although the mechanisms of CRGs in SD immune regulation are less studied, it can be speculated based on previous studies and the results of this study that cuproptosis may play an important role in SD immune infiltration.…”

Section: Discussionmentioning

confidence: 99%

Identification and immuno-infiltration analysis of cuproptosis regulators in human spermatogenic dysfunction

Zhao

Liu

et al. 2023

Front. Genet.

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Introduction: Cuproptosis seems to promote the progression of diverse diseases. Hence, we explored the cuproptosis regulators in human spermatogenic dysfunction (SD), analyzed the condition of immune cell infiltration, and constructed a predictive model.Methods: Two microarray datasets (GSE4797 and GSE45885) related to male infertility (MI) patients with SD were downloaded from the Gene Expression Omnibus (GEO) database. We utilized the GSE4797 dataset to obtain differentially expressed cuproptosis-related genes (deCRGs) between SD and normal controls. The correlation between deCRGs and immune cell infiltration status was analyzed. We also explored the molecular clusters of CRGs and the status of immune cell infiltration. Notably, weighted gene co-expression network analysis (WGCNA) was used to identify the cluster-specific differentially expressed genes (DEGs). Moreso, gene set variation analysis (GSVA) was performed to annotate the enriched genes. Subsequently, we selected an optimal machine-learning model from four models. Finally, nomograms, calibration curves, decision curve analysis (DCA), and the GSE45885 dataset were utilized to verify the predictions’ accuracy.Results: Among SD and normal controls, we confirmed that there are deCRGs and activated immune responses. Through the GSE4797 dataset, we obtained 11 deCRGs. ATP7A, ATP7B, SLC31A1, FDX1, PDHA1, PDHB, GLS, CDKN2A, DBT, and GCSH were highly expressed in testicular tissues with SD, whereas LIAS was lowly expressed. Additionally, two clusters were identified in SD. Immune-infiltration analysis showed the existing heterogeneity of immunity at these two clusters. Cuproptosis-related molecular Cluster2 was marked by enhanced expressions of ATP7A, SLC31A1, PDHA1, PDHB, CDKN2A, DBT, and higher proportions of resting memory CD4+ T cells. Furthermore, an eXtreme Gradient Boosting (XGB) model based on 5-gene was built, which showed superior performance on the external validation dataset GSE45885 (AUC = 0.812). Therefore, the combined nomogram, calibration curve, and DCA results demonstrated the accuracy of predicting SD.Conclusion: Our study preliminarily illustrates the relationship between SD and cuproptosis. Moreover, a bright predictive model was developed.

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Section: Discussionmentioning

confidence: 99%

Identification and immuno-infiltration analysis of cuproptosis regulators in human spermatogenic dysfunction

Zhao

Liu

et al. 2023

Front. Genet.

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“…Thus, a better understanding of immunosenescence and of its molecular mechanisms is needed to improve therapeutic options and mitigate their late-effects on cancer patients. Features of senescence involving the adaptive immune response have been reported in TC survivors treated with three or more cycles of chemotherapy ( 58 ), however, the overall picture of the long-term effect of current TC management on the immune system is still incomplete. Other studies are needed to address how psychological stress caused by the diagnosis and treatment of a life-threatening disease could affect the immune system.…”

Section: Discussionmentioning

confidence: 99%

“…Only one study has been conducted to date on the long-term effects of chemotherapy on the immune system of TC survivors ( 58 ). Bourlon et al.…”

Section: Effect Of Cancer Treatment Regimens On Immunosenescencementioning

confidence: 99%

“…Increase of memory cells number was detected in both CD4+ and CD8+ compartments, whereas memory B cells unexpectedly decreased. Moreover, CD3+ cells expressed higher levels of p16INK4a, suggesting the induction of a senescent phenotype ( 58 ). Even if few cases were analyzed, this is the first study to identify an aged immune system phenotype in TC survivors.…”

Section: Effect Of Cancer Treatment Regimens On Immunosenescencementioning

confidence: 99%

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Immunosenescence in Testicular Cancer Survivors: Potential Implications of Cancer Therapies and Psychological Distress

et al. 2021

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Testicular cancer (TC) is the most frequent solid tumor diagnosed in young adult males. Although it is a curable tumor, it is frequently associated with considerable short-term and long-term morbidity. Both biological and psychological stress experienced during cancer therapy may be responsible for stimulating molecular processes that induce premature aging and deterioration of immune system (immunosenescence) in TC survivors, leading to an increased susceptibility to infections, cancer, and autoimmune diseases. Immunosenescence is a remodeling of immune cell populations with inversion of the CD4:CD8 ratio, accumulation of highly differentiated memory cells, shrinkage of telomeres, shift of T-cell response to Th2 type, and release of pro-inflammatory signals. TC survivors exposed to chemotherapy show features of immunological aging, including an increase in memory T-cells (CD4+ and CD8+) and high expression of the senescence biomarker p16INK4a in CD3+ lymphocytes. However, the plethora of factors involved in the premature aging of TC survivors make the situation more complex if we also take into account the psychological stress and hormonal changes experienced by patients, as well as the high-dose chemotherapy and hematopoietic stem cell transplantation that some individuals may be required to undergo. The relatively young age and the long life expectancy of TC patients bear witness to the importance of improving quality of life and of alleviating long-term side-effects of cancer treatments. Within this context, the present review takes an in-depth look at the molecular mechanisms of immunosenescence, describing experimental evidence of cancer survivor aging and highlighting the interconnected relationship between the many factors modulating the aging of the immune system of TC survivors.

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“…Testicular cancer survivors treated with bleomycin, etoposide, and cisplatin cycles had significantly higher p16 INK4 expression and significantly lower CD4 + and CD8 + counts than age-matched healthy controls (156). (66).…”

Section: Telomere Attritionmentioning

confidence: 93%

The Achilles’ heel of cancer survivors: fundamentals of accelerated cellular senescence

Shafqat¹,

Chicas²,

Shafqat³

et al. 2022

Journal of Clinical Investigation

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Cancer survival times have increased annually owing to advances in early detection and treatment that prolong patient survival. However, increasing survivorship has underscored the observation that cancer survivors develop age-related diseases prematurely, which cause significant morbidity, health expenditures, and mortality. Many cancer survivors have been exposed to chemotherapy, radiotherapy, or both; despite eradicating cancer cells, these therapies also damage normal cells to accelerate biologic aging, such that a discrepancy exists between their biologic and chronologic age (1). Considerable data exist regarding the phenotypes of accelerated aging. However, mechanical and molecular uncertainties have limited the study of these manifestations in a clinical context. Our Review discusses accelerated aging phenotypes in cancer survivors and the cellular mechanisms underpinning these phenomena. We then discuss the translational evidence on how accelerated aging phenotypes, mainly related to senescence, are being targeted while highlighting areas of uncertainty for future research to address.

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Immunosenescence profile and expression of the aging biomarker (p16INK4a) in testicular cancer survivors treated with chemotherapy

Cited by 13 publications

References 20 publications

Identification and immuno-infiltration analysis of cuproptosis regulators in human spermatogenic dysfunction

Identification and immuno-infiltration analysis of cuproptosis regulators in human spermatogenic dysfunction

Immunosenescence in Testicular Cancer Survivors: Potential Implications of Cancer Therapies and Psychological Distress

The Achilles’ heel of cancer survivors: fundamentals of accelerated cellular senescence

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