Cardiomyocytes display low mitochondrial priming and are highly resistant toward cytotoxic T‐cell killing

Zheng, Xiang; Halle, Stephan; Yu, Kai; Mishra, Pooja; Scherr, Michaela; Pietzsch, Stefan; Willenzon, Stefanie; Janssen, Anika; Boelter, Jasmin; Hilfiker‐Kleiner, Denise; Eder, Matthias; Förster, Reinhold

doi:10.1002/eji.201546080

Cited by 6 publications

(3 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further complementary analysis of mitochondrial membrane potential was done using MitoTracker Red CMXRos dye ( Figure 5B ). MitoTracker Red CMXRos dye accumulates in the mitochondria and its accumulation is dependent on mitochondrial membrane potential ( 29 ). Figure 5B shows greater MitoTracker Red dye accumulation in MACS-purified hiPSC-CMs, indicating more hyperpolarized, active mitochondria compared with CMs purified using metabolic stress selection.…”

Section: Resultsmentioning

confidence: 99%

In vitro model of ischemic heart failure using human induced pluripotent stem cell–derived cardiomyocytes

Davis¹,

Chouman²,

Creech³

et al. 2021

JCI Insight

View full text Add to dashboard Cite

show abstract

Section: Resultsmentioning

confidence: 99%

In vitro model of ischemic heart failure using human induced pluripotent stem cell–derived cardiomyocytes

Davis¹,

Chouman²,

Creech³

et al. 2021

JCI Insight

View full text Add to dashboard Cite

show abstract

“…Additive cytotoxicity may provide a mechanism by which dense CTL infiltrates induce apoptosis in a viral infection model 29 or, here, the tumor invasion zone. Alternatively, inefficient sublethal hit delivery may explain failed eradication despite high CTL numbers in solid tumors in mice 5 , during alloimmune response against transplants 30 or, here, subregions of the tumor margin.…”

Section: Discussionmentioning

confidence: 99%

Cancer cell elimination by cytotoxic T cell cooperation and additive damage

Weigelin

Boer

Wagena

et al. 2020

Preprint

View full text Add to dashboard Cite

22Cytotoxic T lymphocytes (CTL) eliminate tumor target cells in an antigen and cell-contact 23 dependent manner. Lethal hit delivery occurs as a rapid and binary, "yes/no" process when 24 immunogenicity is very high 1-3 , however in vivo CTL often fail to kill solid tumor cells 25 during 1:1 conjugations 4-6 . Using long-term time-lapse microscopy in three distinct tumor 26 cytotoxicity models and statistical modeling, we here show that migrating CTL transit 27 between target cells and initiate apoptosis by a series of sublethal interactions ('additive 28 cytotoxicity'), while individual conjugations rarely induced apoptosis. Sublethal damage 29 included perforin-dependent membrane pore formation, nuclear lamina rupture and DNA 30 damage, and these events resolved within minutes to hours. In immunogenic B16F10 31 melanoma tumors in vivo, frequent serial engagements and sublethal hit delivery of CTL 32 was largely confined to interstitial niches in the invasion front, resulting in eradication of 33 invading tumor cells. Thus, additive cytotoxicity is a probabilistic process achieved by a 34 series of CTL-target cell engagements and sublethal events. The need for additive "hits" 35 contacts resulted in the serial killing of multiple neighboring target cells by a single CTL ( Fig. 66 1a; Movie 1). On the population level, 50% of the CTL acted as serial killers (maximum of 11 67 killed target cells/24 h), whereas a small CTL subset (15%) repeatedly contacted target cells 68 without inducing apoptosis (Extended Data Fig. 1e). The percentage of CTL with killing 69 capacity correlated with the surface expression of Lamp-1 by 85% of CTL, indicating 70 recognition of the target cells and lytic vesicle exocytosis by the majority of CTL (Fig. 1b). The 71 lag phase to apoptosis was neither compromised nor accelerated over consecutive killing events 72 ( Fig. 1c), which resulted in a consistent eradication frequency of 1 kill every 2 hours (Extended 73 Data Fig. 1f). This excludes gain of cytotoxicity by kinetic priming through repetitive antigenic 74 interactions. Thus, OT1 CTL serially eliminate highly immunogenic target cells over 24 h and in 75 a non-exhaustive manner. 76 CTL induce sublethal damage 77 To compare effector function against solid tumor cells, which typically retain resistance to CTL 78 mediated killing, OT1 CTL were confronted with mouse melanoma B16F10 cells expressing the 79 OVA peptide (B16F10/OVA) (Extended Data Fig. 2 a-d; Movie 2). As a second model, IL-2 80 activated human SMCY.A2 CTL 14 , which recognize an HLA-A2 restricted antigen encoded on 81 the y chromosome, were confronted with male human melanoma cell lines BLM or MV3 82 (Extended Data Fig. 2 e-i; Movie 3). Compared to the MEC-1/OVA cells, these three 83 melanoma models show delayed, but ultimately effective target cell elimination at the end-point 84 after 24 hours, whereas OVA-negative B16F10 or female MCF-7 cells survived (Fig. 1e). Thus, 85 the endpoints of both murine and human models for probing CTL effector function show 86 compar...

show abstract

“…Evidence for effective serial target cell killing after 1 : 1 pairings has further not been obtained in antigenic solid tumor models in mice where CTLs were found to form predominantly short-lived interactions with target cells, which rarely result in direct apoptosis induction [9][10][11][12][13] . Beyond tumor models, non-productive CTL interactions and failed target cell eradication are also observed in alloimmune response against transplants 14 and murine cytomegalovirus-infected cells in the mouse dermis 15 . Consequently, the physiological relevance of CTL contacts, which-individually-fail to induce target cell death remains unclear.…”

mentioning

confidence: 99%

Cytotoxic T cells are able to efficiently eliminate cancer cells by additive cytotoxicity

et al. 2021

View full text Add to dashboard Cite

Lethal hit delivery by cytotoxic T lymphocytes (CTL) towards B lymphoma cells occurs as a binary, “yes/no” process. In non-hematologic solid tumors, however, CTL often fail to kill target cells during 1:1 conjugation. Here we describe a mechanism of “additive cytotoxicity” by which time-dependent integration of sublethal damage events, delivered by multiple CTL transiting between individual tumor cells, mediates effective elimination. Reversible sublethal damage includes perforin-dependent membrane pore formation, nuclear envelope rupture and DNA damage. Statistical modeling reveals that 3 serial hits delivered with decay intervals below 50 min discriminate between tumor cell death or survival after recovery. In live melanoma lesions in vivo, sublethal multi-hit delivery is most effective in interstitial tissue where high CTL densities and swarming support frequent serial CTL-tumor cell encounters. This identifies CTL-mediated cytotoxicity by multi-hit delivery as an incremental and tunable process, whereby accelerating damage magnitude and frequency may improve immune efficacy.

show abstract

Cardiomyocytes display low mitochondrial priming and are highly resistant toward cytotoxic T‐cell killing

Cited by 6 publications

References 40 publications

In vitro model of ischemic heart failure using human induced pluripotent stem cell–derived cardiomyocytes

In vitro model of ischemic heart failure using human induced pluripotent stem cell–derived cardiomyocytes

Cancer cell elimination by cytotoxic T cell cooperation and additive damage

Cytotoxic T cells are able to efficiently eliminate cancer cells by additive cytotoxicity

Contact Info

Product

Resources

About