Senescent Tumor CD8+ T Cells: Mechanisms of Induction and Challenges to Immunotherapy

Liu, Wei; Stachura, Paweł; Xu, Haifeng; Bhatia, Sanil; Lang, Philipp A.; Pandyra, Aleksandra A.

doi:10.3390/cancers12102828

Cited by 13 publications

(14 citation statements)

References 95 publications

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“…Senescent T cells share several common features with senescent somatic cells. Senescent T cells become larger and flatter and show positive senescence-associated β-galactosidase (SA-β-gal) staining [ 4 , [11] , [12] , [13] , [14] ]. The telomeres become shortened and the DNA damage increases, which then leads to the upregulation of p53, p21, and p16, and the downregulation of Cdk2, Cdk6, and cyclin D3 to cause cell cycle arrest [ [11] , [12] , [13] , 15 ].…”

Section: Characteristics and Potential Roles Of Senescent T Cells In Tumoursmentioning

confidence: 99%

“…In addition to the common features mentioned above, senescent T cells show distinct surface markers. Senescent T cells lose the expression of costimulatory receptors CD27/CD28 but express CD57 and KLRG-1, which indicates replicative senscent [2] , [3] , [4] . Senescent T cells also show a terminally differentiated phenotype with the downregulation of the chemokine receptors CCR7 and CD45RO but the upregulation of CD45RA [ 17 , 22 , 23 ].…”

Section: Characteristics and Potential Roles Of Senescent T Cells In Tumoursmentioning

confidence: 99%

“…The principle features of exhausted T cells is the elevated inhibitory receptors, including programmed cell death protein 1 (PD-1), T cell immunoglobulin and mucin domain containing-3 (Tim-3), and lymphocyte activation gene-3 (LAG-3) with impaired cytotoxicity and effector cytokine production [1] . Senescent T cells have a distinct phenotypes including downregulated expression of the costimulatory molecules CD27 and CD28, and high expression of CD57, killer cell lectin-like receptor subfamily G member 1 (KLRG-1), and CD45RA [2] , [3] , [4] . They share common features with senescent somatic cells such as DNA damage, declines in proliferation and activation, but are able to produce high amounts of proinflammatory cytokines [5] .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Senescent T cells: a potential biomarker and target for cancer therapy

Zhang

Xue

et al. 2021

EBioMedicine

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The failure of T cells to eradicate tumour cells in the tumour microenvironment is mainly due to the dysfunction of T cells. Senescent T cells, with defects in proliferation and effector functions, accumulate in ageing, chronic viral infections, and autoimmune disorders where antigen stimulation persists. Increasing evidence suggests that inducing T cell senescence is a key strategy used by malignant tumours to evade immune surveillance. In this review, we summarize the general features, functional regulation, and signalling network of senescent T cells in tumour development and highlight their potential as prognostic biomarkers in multiple cancer treatments, including chemotherapy, radiotherapy, and immunotherapy. Moreover, we discuss possible therapeutic strategies for preventing or rejuvenating senescence in tumour-specific T cells. Understanding these critical issues may provide novel strategies to enhance cancer immunotherapy.

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Section: Characteristics and Potential Roles Of Senescent T Cells In Tumoursmentioning

confidence: 99%

Section: Characteristics and Potential Roles Of Senescent T Cells In Tumoursmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Senescent T cells: a potential biomarker and target for cancer therapy

Zhang

Xue

et al. 2021

EBioMedicine

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“…Following tumor infiltration, T cells interact with other immune, cancer, and stromal cells within the tumor microenvironment (TME). Cells comprised in this environment may develop premature senescence caused by external factors such as TME metabolic changes or drug and radiation therapy [ 173 ]. Senescent cells stay metabolically active but cease to proliferate [ 174 , 175 ].…”

Section: Biology Meets Therapy: T-cell Dysfunction In Adoptive Celmentioning

confidence: 99%

T-Cell Dysfunction as a Limitation of Adoptive Immunotherapy: Current Concepts and Mitigation Strategies

Janelle

Delisle

2021

Cancers

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Over the last decades, cellular immunotherapy has revealed its curative potential. However, inherent physiological characteristics of immune cells can limit the potency of this approach. Best defined in T cells, dysfunction associated with terminal differentiation, exhaustion, senescence, and activation-induced cell death, undermine adoptive cell therapies. In this review, we concentrate on how the multiple mechanisms that articulate the various forms of immune dysfunction impact cellular therapies primarily involving conventional T cells, but also other lymphoid subtypes. The repercussions of immune cell dysfunction across the full life cycle of cell therapy, from the source material, during manufacturing, and after adoptive transfer, are discussed, with an emphasis on strategies used during ex vivo manipulations to limit T-cell dysfunction. Applicable to cellular products prepared from native and unmodified immune cells, as well as genetically engineered therapeutics, the understanding and potential modulation of dysfunctional features are key to the development of improved cellular immunotherapies.

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“…Following tumor infiltration, T cells interact with other immune, cancer and stromal cells within the tumor microenvironment (TME). Cells comprised in this environment may develop premature senescence caused by external factors such as TME metabolic changes or drug and radiation therapy [158]. Senescent cells will stay metabolically active but will cease to proliferate [159,160].…”

Section: Tumor-infiltrating Lymphocytesmentioning

confidence: 99%

Advances in Cellular Immunotherapy: Understanding and Preventing T-cell Dysfunction

Janelle¹,

Delisle²

2020

Preprint

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Over the last decades, cellular immunotherapy has revealed its curative potential. However, the inherent physiological characteristics of immune cells can limit the potency of this approach. Best defined in T cells, dysfunction associated with terminal differentiation, exhaustion, senescence, and activation-induced cell death undermine adoptive cell therapies. In this review, we concentrate on how the multiple mechanisms that articulate the various forms of immune dysfunction impact cellular therapies primarily involving conventional T cells, but also other lymphoid subtypes, in addition to the various strategies put in place to circumvent these effects. The repercussions of immune cell dysfunction across the full life cycle of cell therapy, from the source material, during manufacturing, and after adoptive transfer are discussed. Applicable to cellular products prepared from native and unmodified immune cells, as well as genetically engineered therapeutics, the understanding and potential modulation of dysfunctional features is key to the development of improved cellular immunotherapies.

show abstract

Senescent Tumor CD8+ T Cells: Mechanisms of Induction and Challenges to Immunotherapy

Cited by 13 publications

References 95 publications

Senescent T cells: a potential biomarker and target for cancer therapy

Senescent T cells: a potential biomarker and target for cancer therapy

T-Cell Dysfunction as a Limitation of Adoptive Immunotherapy: Current Concepts and Mitigation Strategies

Advances in Cellular Immunotherapy: Understanding and Preventing T-cell Dysfunction

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