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The Bright and Dark Sides of Apoptosis and Other Modes of Cell “Death” in Cancer Therapy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 26462

Special Issue Editor

Special Issue Information

Dear Colleagues,

Stress-induced programmed cell death (e.g., through apoptosis) and “functional death” (e.g., dormancy through premature senescence) in cancer cells have long been regarded as favorable outcomes in cancer therapy. In the past decade, however, it has become evident that while these responses are essential for initial tumor control, they can also contribute to disease relapse, at least in solid tumors. Apoptotic cancer cells, for example, not only secrete tumor-promoting factors but can also undergo a reversal process (through anastasis), giving rise to tumor repopulating progeny. Reversal of a subset of apoptotic/dormant cancer cells contributes to intratumor heterogeneity, which poses a major challenge in treating cancer patients with metastatic disease. Unfortunately, intratumor heterogeneity is overlooked in most preclinical methods used in anticancer studies.

The purpose of this Special Issue is to provide a comprehensive update on molecular events that underlie intratumor heterogeneity in the context of cancer therapy. Reviews and original articles addressing the dark side of stress-induced apoptosis and senescence in solid tumors are particularly welcomed.

Prof. Dr. Razmik Mirzayans
Guest Editor

Manuscript Submission Information

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Keywords

  • intratumor heterogeneity
  • single-cell analysis
  • senescence
  • senotherapeutics
  • apoptosis and tumorigenicity
  • anastasis
  • cell fusion
  • novel therapeutic strategies targeting dormant cancer cells

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Published Papers (6 papers)

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Research

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14 pages, 2325 KiB  
Communication
Profiling Anti-Apoptotic BCL-xL Protein Expression in Glioblastoma Tumorspheres
by Deborah Fanfone, Ahmed Idbaih, Jade Mammi, Mathieu Gabut and Gabriel Ichim
Cancers 2020, 12(10), 2853; https://doi.org/10.3390/cancers12102853 - 2 Oct 2020
Cited by 22 | Viewed by 3633
Abstract
Glioblastoma (GBM) is one of the cancers with the worst prognosis, despite huge efforts to understand its unusual heterogeneity and aggressiveness. This is mainly due to glioblastoma stem cells (GSCs), which are also responsible for the frequent tumor recurrence following surgery, chemotherapy or [...] Read more.
Glioblastoma (GBM) is one of the cancers with the worst prognosis, despite huge efforts to understand its unusual heterogeneity and aggressiveness. This is mainly due to glioblastoma stem cells (GSCs), which are also responsible for the frequent tumor recurrence following surgery, chemotherapy or radiotherapy. In this study, we investigate the expression pattern of the anti-apoptotic BCL-xL protein in several GBM cell lines and the role it might play in GSC-enriched tumorspheres. We report that several GBM cell lines have an increased BCL-xL expression in tumorspheres compared to differentiated cells. Moreover, by artificially modulating BCL-xL expression, we unravel a correlation between BCL-xL and tumorsphere size. In addition, BCL-xL upregulation appears to sensitize GBM tumorspheres to newly developed BH3 mimetics, opening promising therapeutic perspectives for treating GBM patients. Full article
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Graphical abstract

Graphical abstract
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<p>Evaluation of BCL-xL expression in tumorspheres versus differentiated cells in various commercially available and glioblastoma (GBM) patient-derived cell lines. (<b>A</b>) Images of GBM cell lines cultured as differentiated cells or tumorspheres. Magnification: 2.5X – 5X. (<b>B</b>) Western blot analysis of BCL-xL expression in commercially available and GBM patient-derived cell lines. Full-length blots are presented in <a href="#app1-cancers-12-02853" class="html-app">Figure S4</a>. (<b>C</b>) Densitometry analysis of BCL-xL expression in tumorspheres (ratio to differentiated cells) distinguishing three categories of BCL-xL expression: high, moderate and equal or lower BCL-xL expression in GBM tumorspheres.</p>
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<p>BCL-xL is highly expressed in U-87 MG-derived tumorspheres compared to differentiated cells. (<b>A</b>) qRT-PCR analysis of selected GSCs signature markers (OLIG2, ITGA6, FABP7, PROM1) in U-87 MG cells, grown as differentiated or tumorspheres (data represent mean with SEM from three independent experiments, one-way ANOVA, * <span class="html-italic">p</span> ≤ 0.05, *** <span class="html-italic">p</span> ≤ 0.001, **** <span class="html-italic">p</span> ≤ 0.0001). (<b>B</b>) Western blot analysis of BCL-xL and MCL-1 expression in U-87 MG cells (differentiated versus tumorspheres). Full-length blots are presented in <a href="#app1-cancers-12-02853" class="html-app">Figure S4</a>. (<b>C</b>) qRT-PCR analysis of <span class="html-italic">BCL2L1</span> and <span class="html-italic">MCL1</span> mRNA expression in differentiated cells and tumorspheres grown from U-87 MG cells at 7 and 14 days in culture (data represent mean with SEM from three independent experiments, one-way ANOVA, ns <span class="html-italic">p</span> &gt; 0.05, * <span class="html-italic">p</span> ≤ 0.05). (<b>D</b>) Western blot analysis of BCL-xL to test the influence of various growth factors used to grow tumorspheres. Full-length blots are presented in <a href="#app1-cancers-12-02853" class="html-app">Figure S4</a>.</p>
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<p>BCL-xL overexpression increases the size of U-87 MG-derived tumorspheres. (<b>A</b>) Western blot analysis correlating the expression of BCL-xL with the concentration of Shield-1 ligand used to treat U-87 MG BCL-xL DD cells for 24 h. Full-length blots are presented in <a href="#app1-cancers-12-02853" class="html-app">Figure S4</a>. (<b>B</b>) Western blot analysis of BCL-xL overexpression in U-87 MG tumorspheres after 7 and 14 days of Shield-1 treatment. Full-length blots are presented in <a href="#app1-cancers-12-02853" class="html-app">Figure S4</a>. (<b>C</b>) Representative pictures of U-87 MG tumorspheres following 7 and 14 days of culture in the presence of Shield-1. Magnification: 2.5X. (<b>D</b>,<b>E</b>) Comparison of the size of U-87 MG tumorspheres after 7 (<b>D</b>) or 14 (<b>E</b>) days of culture with and without Shield-1. The solid and dotted lines represent the median and the quartile, respectively, **** <span class="html-italic">p</span> ≤ 0.0001. (<b>F</b>) qRT-PCR analysis of the expression of GSC signature markers (OLIG2, ITGA6, FABP7, PROM1) in U-87 MG cells cultured in the absence or presence of Shield-1 (data represent mean with SEM from three independent experiments, one-way ANOVA, ns <span class="html-italic">p</span> &gt; 0.05). The GSC mRNA signatures from untreated tumorspheres correspond to data described in <a href="#cancers-12-02853-f002" class="html-fig">Figure 2</a>.</p>
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<p>BCL-xL knockdown reduces GBM tumorsphere size. (<b>A</b>) Western blot analysis of BCL-xL expression in differentiated or U-87 MG-derived tumorspheres following shRNA-mediated BCL-xL knock-down. Two different specific shRNAs resulted in the same silencing efficacy. Full-length blots are presented in <a href="#app1-cancers-12-02853" class="html-app">Figure S4</a>. (<b>B</b>) Representative images of U-87 MG tumorspheres after BCL-xL silencing. Magnification: 2.5X. (<b>C</b>) Comparison of the size of U-87 MG tumorspheres before and after BCL-xL knockdown. The solid and dotted lines represent the median and the quartile, respectively, **** <span class="html-italic">p</span> ≤ 0.0001. (<b>D</b>) qRT-PCR analysis of the expression of GSC signature markers (OLIG2, FABP7, ITGA6) in control cells versus BCL-xL knockdown tumorspheres (data represent the mean with SEM from three independent experiments, one-way ANOVA, ns <span class="html-italic">p</span> &gt; 0.05).</p>
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<p>U-87 MG tumorspheres have an increased sensitivity to ABT-263-induced apoptosis. (<b>A</b>) Brief summary of the main BH3 mimetics and their preferential targets. (<b>B</b>) IncuCyte imager-based cell death induction analysis of U-87 MG-derived tumorspheres treated with ABT-737, ABT-263 or S63845 as indicated. Induction of apoptosis was assessed by SYTOX Green incorporation into permeabilized dead cells. (<b>C</b>) Representative pictures of U-87 MG tumorspheres treated with different BH3 mimetics, while the green signal indicates SYTOX Green-positive apoptotic cells Magnification: 4X. (<b>D</b>) Western blot analysis of PARP-1 and caspase-3 protein expression and cleavage following treatment with BH3 mimetics. Full-length blots are presented in <a href="#app1-cancers-12-02853" class="html-app">Figure S4</a>. (<b>E</b>) Representative images of U-87 MG tumorspheres in a long-term survival assay. Briefly, following treatment with the indicated BH3 mimetics, U-87 MG-derived tumorspheres were cultured in fresh medium for another week and imaged. Magnification: 2.5X. (<b>F</b>) Quantification of tumorsphere number for the long-term survival assay described in (<b>E</b>) (data represent mean with SEM from three independent experiments, one-way ANOVA, ns <span class="html-italic">p</span> &gt; 0.05, *** <span class="html-italic">p</span> ≤ 0.001, **** <span class="html-italic">p</span> ≤ 0.0001). (<b>G</b>) qRT-PCR analysis for the GSC signature of U-87 MG tumorspheres treated with ATB-263 (data represent mean with SEM from three independent experiments, one-way ANOVA, ns <span class="html-italic">p</span> &gt; 0.05, * <span class="html-italic">p</span> ≤ 0.05, ** <span class="html-italic">p</span> ≤ 0.01, **** <span class="html-italic">p</span> ≤ 0.0001).</p>
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Review

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24 pages, 2425 KiB  
Review
Cell-Cell Fusion Mediated by Viruses and HERV-Derived Fusogens in Cancer Initiation and Progression
by Thomas Dittmar, Julian Weiler, Tianjiao Luo and Ralf Hass
Cancers 2021, 13(21), 5363; https://doi.org/10.3390/cancers13215363 - 26 Oct 2021
Cited by 25 | Viewed by 4275
Abstract
Cell fusion is a well-known, but still scarcely understood biological phenomenon, which might play a role in cancer initiation, progression and formation of metastases. Although the merging of two (cancer) cells appears simple, the entire process is highly complex, energy-dependent and tightly regulated. [...] Read more.
Cell fusion is a well-known, but still scarcely understood biological phenomenon, which might play a role in cancer initiation, progression and formation of metastases. Although the merging of two (cancer) cells appears simple, the entire process is highly complex, energy-dependent and tightly regulated. Among cell fusion-inducing and -regulating factors, so-called fusogens have been identified as a specific type of proteins that are indispensable for overcoming fusion-associated energetic barriers and final merging of plasma membranes. About 8% of the human genome is of retroviral origin and some well-known fusogens, such as syncytin-1, are expressed by human (cancer) cells. Likewise, enveloped viruses can enable and facilitate cell fusion due to evolutionarily optimized fusogens, and are also capable to induce bi- and multinucleation underlining their fusion capacity. Moreover, multinucleated giant cancer cells have been found in tumors derived from oncogenic viruses. Accordingly, a potential correlation between viruses and fusogens of human endogenous retroviral origin in cancer cell fusion will be summarized in this review. Full article
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Figure 1

Figure 1
<p>A hypothetic model of potential virus-mediated stepwise (cancer) cell fusion suggests the formation of diaphragm intermediates by the initial merging of the outer lipid layers of adjacent plasma membranes as hemifusion. Expression of fusogenic factors, e.g., syncytin-1 and the corresponding receptor alanine, serine, and cysteine selective transporter-2 (ASCT-2), together with other viral fusogens such as human endogenous retroviruses (HERV) proteins and further cell fusion inducing factors, such as tumor necrosis factor-α (TNF-α), is required within the cellular fusion partners. Concomitantly, intracellular restructuring of actin cytoskeletal proteins together with an ion gradient and low pH provide a fusion-permissive microenvironment. As a prerequisite, the plasma membranes of the somatic or cancer cells fusion partners in cooperation with the membrane of enveloped viruses have to be localized in close proximity whereby extension of membrane protrusions as lamellipodia can form local fusion pores. Whereas viruses can act as a linker for bridging fusogenic cell membranes the precise molecular role of enveloped viruses to contribute to outer membrane opening, formation of an intermediate hemifusion state, and finally the opening of the inner membrane lipid layers remains enigmatic. Among the various membrane lipids phosphatidylserine (PS) plays an important role in altering the inner lipid membrane structures to enable and finalize the fusion process. Thereby, PS interacts with associated proteins such as annexin V, scramblases, and various cytoskeletal components.</p>
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<p>Changes in the karyotype during HST/PR by lagging chromosomes and multipolar divisions with formation of multinucleation and micronuclei and chromothripsis. Shown are representative images of hybrid cells derived from M13SV1 human breast epithelial cells that were stably transduced with pH2B-GFP (kind gift from Geoff Wahl; Addgene plasmid #11680; <a href="http://n2t.net/addgene:11680" target="_blank">http://n2t.net/addgene:11680</a>; RRID: Addgene_11680) or pH2B_mCherry_IRES_puro2 (kind gift from Daniel Gerlich; Addgene plasmid #21045; <a href="http://n2t.net/addgene:21045" target="_blank">http://n2t.net/addgene:21045</a>; RRID:Addgene_21045). The plasmids were used to trace green fluorescing GFP-expressing cells and red fluorescing mCherry expressing cells that eventually fuse by forming yellow fluorescing hybrid cells with constitutive expression of both fluorescence genes. Hybrid cells were cultured on chamber slides (ThermoFisher Scientific GmbH, Schwerte, Germany) and images and time-lapse series were recorded using a Leica TCS SP5 confocal laser scanning microscope (Leica, Wetzlar, Germany). Multiple nuclei in multinucleated cells were marked by a dashed line. The arrow points to a micronucleus. Video files of the tri- and tetrapolar cell divisions can be found in the <a href="#app1-cancers-13-05363" class="html-app">Supplementary Materials Videos S1 and S2</a>, respectively. Bar = 25 µm.</p>
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20 pages, 1654 KiB  
Review
Cancer Cell Fusion and Post-Hybrid Selection Process (PHSP)
by Ralf Hass, Juliane von der Ohe and Thomas Dittmar
Cancers 2021, 13(18), 4636; https://doi.org/10.3390/cancers13184636 - 16 Sep 2021
Cited by 20 | Viewed by 4694
Abstract
Fusion of cancer cells either with other cancer cells (homotypic fusion) in local vicinity of the tumor tissue or with other cell types (e.g., macrophages, cancer-associated fibroblasts (CAFs), mesenchymal stromal-/stem-like cells (MSC)) (heterotypic fusion) represents a rare event. Accordingly, the clinical relevance of [...] Read more.
Fusion of cancer cells either with other cancer cells (homotypic fusion) in local vicinity of the tumor tissue or with other cell types (e.g., macrophages, cancer-associated fibroblasts (CAFs), mesenchymal stromal-/stem-like cells (MSC)) (heterotypic fusion) represents a rare event. Accordingly, the clinical relevance of cancer-cell fusion events appears questionable. However, enhanced tumor growth and/or development of certain metastases can originate from cancer-cell fusion. Formation of hybrid cells after cancer-cell fusion requires a post-hybrid selection process (PHSP) to cope with genomic instability of the parental nuclei and reorganize survival and metabolic functionality. The present review dissects mechanisms that contribute to a PHSP and resulting functional alterations of the cancer hybrids. Based upon new properties of cancer hybrid cells, the arising clinical consequences of the subsequent tumor heterogeneity after cancer-cell fusion represent a major therapeutic challenge. However, cellular partners during cancer-cell fusion such as MSC within the tumor microenvironment or MSC-derived exosomes may provide a suitable vehicle to specifically address and deliver anti-tumor cargo to cancer cells. Full article
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Figure 1
<p>Cancer-cell fusion in vitro. Cancer-cell fusion of cherry-labeled human MDA-MB-231 breast-cancer cells (<b>left</b> panel) with the GFP-labeled human MSC544 cell line in P34 (<b>middle</b> panel) was detectable following a 4 day co-culture similar to previous experimental approaches [<a href="#B45-cancers-13-04636" class="html-bibr">45</a>]. Two evolving breast-cancer hybrid cells became detectable after spontaneous fusion (white arrows), which simultaneously expressed the cherry (<b>left</b> panel) and GFP genes (<b>middle</b> panel) in a fluorescence overlay by displaying a yellow color (<b>right</b> panel). Bars represent 200 µm using a BZ-X800 Keyence fluorescence microscope.</p>
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<p>Different pathways within a PHSP are suggested to include subsequent intermediate steps: 1. regulation of aneuploidy; 2. HST/PR; 3. autocatalytic karyotype evolution; 4a. induction of senescence or apoptosis/necroptosis in a majority of hybrid cells that are unable to survive due to uncoordinated HST/PR; 4b. proliferation of new cancer cells, some of which can carry potential stem-cell properties including radio-/chemoresistance.</p>
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21 pages, 1609 KiB  
Review
Hybrid Formation and Fusion of Cancer Cells In Vitro and In Vivo
by Ralf Hass, Juliane von der Ohe and Thomas Dittmar
Cancers 2021, 13(17), 4496; https://doi.org/10.3390/cancers13174496 - 6 Sep 2021
Cited by 21 | Viewed by 4188
Abstract
The generation of cancer hybrid cells by intra-tumoral cell fusion opens new avenues for tumor plasticity to develop cancer stem cells with altered properties, to escape from immune surveillance, to change metastatic behavior, and to broaden drug responsiveness/resistance. Genomic instability and chromosomal rearrangements [...] Read more.
The generation of cancer hybrid cells by intra-tumoral cell fusion opens new avenues for tumor plasticity to develop cancer stem cells with altered properties, to escape from immune surveillance, to change metastatic behavior, and to broaden drug responsiveness/resistance. Genomic instability and chromosomal rearrangements in bi- or multinucleated aneuploid cancer hybrid cells contribute to these new functions. However, the significance of cell fusion in tumorigenesis is controversial with respect to the low frequency of cancer cell fusion events and a clonal advantage of surviving cancer hybrid cells following a post-hybrid selection process. This review highlights alternative processes of cancer hybrid cell development such as entosis, emperipolesis, cannibalism, therapy-induced polyploidization/endoreduplication, horizontal or lateral gene transfer, and focusses on the predominant mechanisms of cell fusion. Based upon new properties of cancer hybrid cells the arising clinical consequences of the subsequent tumor heterogeneity after cancer cell fusion represent a major therapeutic challenge. Full article
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Figure 1

Figure 1
<p>The formation of cancer hybrid cells is composed of an orchestrated sequence of distinct cellular programs which can be distinguished as (i) a pre-hybrid preparation process (PHPP), (ii) the cancer cell hybridization process, and (iii) a subsequent post-hybrid selection process (PHSP). Several events can lead to cancer cell hybridization including the fusion of cancer cells with neighboring cancer cells (homotypic fusion) or with other cell types (e.g., macrophages, cancer-associated fibroblasts (CAFs), MSC) within the tumor microenvironment (heterotypic fusion).</p>
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<p>Different fates of merged cells. Cell cannibalism (<b>A</b>), emperipolesis (<b>B</b>), and entosis (<b>C</b>) belong to the so-called cell-in-cell phenomena, which are characterized by the engulfment of intact cells. In contrast, cell fusion (<b>D</b>) gives rise to bi- or multinucleated heterokaryons due to merging of the cells’ plasma membranes. Cell cannibalism (<b>A</b>) resembles “phagocytosis” and usually results in the lysosomal digestion of the engulfed cell. In contrast, in emperipolesis (<b>B</b>) and entosis (<b>C</b>) one cell actively invades another cell, whereby the fate of the engulfed cell differs markedly between processes. Emperipolesis is characterized by cells either escaping from the host cell, being destroyed by the host cell, or vice versa destroying the host cell (<b>B</b>). On the contrary, most entotic cells are usually destroyed by lysosomal degradation, whereas some internalized cells may also survive and can even divide within the host cell (<b>C</b>). Moreover, entosis may be associated with aberrant mitosis (<b>E</b>) and the origin of aneuploid and genomic instable daughter cells. A characteristic of hybrid cells is the merging of parental chromosomes and their random segregation to daughter cells during bi- and multipolar divisions (<b>F</b>), which is also associated with aneuploidy, genomic instability, and micronucleus formation.</p>
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18 pages, 1264 KiB  
Review
Anastasis: Return Journey from Cell Death
by Victoria Zaitceva, Gelina S. Kopeina and Boris Zhivotovsky
Cancers 2021, 13(15), 3671; https://doi.org/10.3390/cancers13153671 - 22 Jul 2021
Cited by 22 | Viewed by 4446
Abstract
For over 20 years, it has been a dogma that once the integrity of mitochondria is disrupted and proapoptotic proteins that are normally located in the intermembrane space of mitochondria appeared in the cytoplasm, the process of cell death becomes inevitable. However, it [...] Read more.
For over 20 years, it has been a dogma that once the integrity of mitochondria is disrupted and proapoptotic proteins that are normally located in the intermembrane space of mitochondria appeared in the cytoplasm, the process of cell death becomes inevitable. However, it has been recently shown that upon removal of the death signal, even at the stage of disturbance in the mitochondria, cells can recover and continue to grow. This phenomenon was named anastasis. Here, we will critically discuss the present knowledge concerning the mechanisms of cell death reversal, or development of anastasis, methods for its detection, and what role signaling from different intracellular compartments plays in anastasis stimulation. Full article
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Figure 1
<p>The possible role of mitochondrial heterogeneity in anastasis. The low cardiolipin-contained mitochondria are more resistant to death signals rather than high cardiolipin-contained mitochondria and can therefore be a source of energy for anastasis.</p>
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<p>Summary of key events in cells during anastasis. Anastasis can be divided into early and late stages at which different molecular processes dominate. Eventually, cells after anastasis acquire new mutations which make them more prone to recurrence and metastasis after chemotherapy.</p>
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<p>Micronucleus fate in surviving cells. Post-anastasis cells show the increased formation of micronuclei, which is a marker of DNA damage. However, micronuclei could contribute to maintaining genomic integrity by providing DNA material for homologous recombination or be used as a resource of energy in case of a failure to find sequence homology in micronuclei.</p>
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15 pages, 638 KiB  
Review
Senescent Tumor CD8+ T Cells: Mechanisms of Induction and Challenges to Immunotherapy
by Wei Liu, Paweł Stachura, Haifeng C. Xu, Sanil Bhatia, Arndt Borkhardt, Philipp A. Lang and Aleksandra A. Pandyra
Cancers 2020, 12(10), 2828; https://doi.org/10.3390/cancers12102828 - 30 Sep 2020
Cited by 11 | Viewed by 4001
Abstract
The inability of tumor-infiltrating T lymphocytes to eradicate tumor cells within the tumor microenvironment (TME) is a major obstacle to successful immunotherapeutic treatments. Understanding the immunosuppressive mechanisms within the TME is paramount to overcoming these obstacles. T cell senescence is a critical dysfunctional [...] Read more.
The inability of tumor-infiltrating T lymphocytes to eradicate tumor cells within the tumor microenvironment (TME) is a major obstacle to successful immunotherapeutic treatments. Understanding the immunosuppressive mechanisms within the TME is paramount to overcoming these obstacles. T cell senescence is a critical dysfunctional state present in the TME that differs from T cell exhaustion currently targeted by many immunotherapies. This review focuses on the physiological, molecular, metabolic and cellular processes that drive CD8+ T cell senescence. Evidence showing that senescent T cells hinder immunotherapies is discussed, as are therapeutic options to reverse T cell senescence. Full article
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Figure 1
<p>Surface phenotypic, metabolic and transcriptional differences between CD8<sup>+</sup> dysfunctional senescent and exhaustive states. Characteristics common to both dysfunctional states are shown the in the middle, purple overlapping section. While both T cell state exhibit decreased effector function, senescent T cells have a very distinct senescence-associated secretory phenotype (SASP) with increased cytokine production of IFN-γ, IL-6, IL-8, IL-10, TNF and TGF-β. In contrast. exhausted T cells are characterized by decreased IL-2, TNF and IFN-γ production. While some surface markers such as Tim-3 and TGIT are common to both dysfunctional T cell states, there is otherwise quite a distinct pattern of expression. Ag = antigen.</p>
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<p>T cell senescence can occur via multiple mechanisms within the tumor microenvironment. Tregs, through glucose metabolic competition and transfer of cAMP produced by tumors, can induce CD8<sup>+</sup> T cell senescence, as can other metabolites produced by tumor cells, such as adenosine. Repeated antigen stimulation and external factors such as chemotherapeutic and radiation therapy also induce premature senescence. A key molecular pathway involved in CD8<sup>+</sup> T cell senescence induction is non-canonical signaling through p38-MAPK.</p>
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