Actin remodeling and vesicular trafficking at the tumor cell side of the immunological synapse direct evasion from cytotoxic lymphocytes

Biolato, Andrea Michela; Filali, Liza; Wurzer, Hannah; Hoffmann, Céline; Gargiulo, Ernesto; Valitutti, Salvatore; Thomas, Clément

doi:10.1016/bs.ircmb.2020.07.001

Cited by 11 publications

(6 citation statements)

References 215 publications

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“…The cytoskeleton changes and secretory traffic occurring at the tumor side indeed contribute to modulating the T lymphocyte immune response at the IS, and ultimately may facilitate the escape of tumor cells to the immune control ( 115 , 116 ). These events include cortical actin cytoskeleton reorganization ( 115 ) and may involve polarized traffic of MVBs and exosome secretion [among other polarized secretion events reviewed in ( 116 )] at the synaptic cleft from the tumor side ( 117 ). Based on the fact that tumor cells can recruit and polarize their actin cytoskeleton and secretory lysosomal compartment to the IS, neutralizing CTL cytotoxicity ( 116 , 118 ), it is conceivable that they also have the capability to polarize MVB and to focus immunoregulatory exosome secretion to the IS ( 117 ).…”

Section: Current Research Gapsmentioning

confidence: 99%

“…These events include cortical actin cytoskeleton reorganization ( 115 ) and may involve polarized traffic of MVBs and exosome secretion [among other polarized secretion events reviewed in ( 116 )] at the synaptic cleft from the tumor side ( 117 ). Based on the fact that tumor cells can recruit and polarize their actin cytoskeleton and secretory lysosomal compartment to the IS, neutralizing CTL cytotoxicity ( 116 , 118 ), it is conceivable that they also have the capability to polarize MVB and to focus immunoregulatory exosome secretion to the IS ( 117 ). However, a formal relationship between actin cytoskeleton and polarized MVB secretory traffic such as the existing in T lymphocytes or NK cells, both in effector Th or cytolytic synapses, has not been formally demonstrated yet to occur in tumor cells forming IS.…”

Section: Current Research Gapsmentioning

confidence: 99%

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Extracellular vesicles and microvilli in the immune synapse

Ruiz-Navarro,

Calvo,

Izquierdo

2024

Front. Immunol.

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T cell receptor (TCR) binding to cognate antigen on the plasma membrane of an antigen-presenting cell (APC) triggers the immune synapse (IS) formation. The IS constitutes a dedicated contact region between different cells that comprises a signaling platform where several cues evoked by TCR and accessory molecules are integrated, ultimately leading to an effective TCR signal transmission that guarantees intercellular message communication. This eventually leads to T lymphocyte activation and the efficient execution of different T lymphocyte effector tasks, including cytotoxicity and subsequent target cell death. Recent evidence demonstrates that the transmission of information between immune cells forming synapses is produced, to a significant extent, by the generation and secretion of distinct extracellular vesicles (EV) from both the effector T lymphocyte and the APC. These EV carry biologically active molecules that transfer cues among immune cells leading to a broad range of biological responses in the recipient cells. Included among these bioactive molecules are regulatory miRNAs, pro-apoptotic molecules implicated in target cell apoptosis, or molecules triggering cell activation. In this study we deal with the different EV classes detected at the IS, placing emphasis on the most recent findings on microvilli/lamellipodium-produced EV. The signals leading to polarized secretion of EV at the synaptic cleft will be discussed, showing that the IS architecture fulfills a fundamental task during this route.

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Section: Current Research Gapsmentioning

confidence: 99%

Section: Current Research Gapsmentioning

confidence: 99%

Extracellular vesicles and microvilli in the immune synapse

Ruiz-Navarro,

Calvo,

Izquierdo

2024

Front. Immunol.

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“…Cancer cells have evolved defense responses to evade lymphocyte cytotoxicity, such as rapid polarization of their actin cytoskeleton and vesicles toward the immunological synapse. 4 , 5 , 6 Characterization of the signaling pathways controlling the key cellular processes at both pre- and post-synaptic sides of the immunological synapse is essential to develop novel strategies aimed at improving cytotoxic lymphocyte immune response.…”

Section: Before You Beginmentioning

confidence: 99%

An integrated workflow for phosphopeptide identification in natural killer cells (NK-92MI) and their targets (MDA-MB-231) during immunological synapse formation

et al. 2023

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“…Importantly, this process of synaptic membrane repair is ultra-rapid and calcium-dependent; high spatio-temporal resolution single-cell imaging has demonstrated that a calcium signal propagates outwards from hotspots in the IS within milliseconds and that calcium chelation drastically increases CTL-mediated cytotoxicity by inhibiting synaptic repair mechanisms ( 57 ). In a similar scenario, actin remodeling has also been shown to mediate breast cancer cell resistance to NK cell-derived cytotoxic molecules ( 144 , 145 ); in these studies, a live F-actin probe was utilized to demonstrate the massive accumulation of actin at the IS in resistant but not susceptible target cells and this synaptic actin accumulation occurred very rapidly (<2min) ( 144 ). Interestingly, the actin response persisted throughout the entire contact time between the NK cell and the tumor cell and dissipated following the detachment of the attack NK cell ( 144 ).…”

Section: Cellular Defense Mechanisms Against Ctl Attackmentioning

confidence: 99%

Greek Fire, Poison Arrows, and Scorpion Bombs: How Tumor Cells Defend Against the Siege Weapons of Cytotoxic T Lymphocytes

2022

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CD8+ cytotoxic T lymphocytes (CTLs) are the main cellular effectors of the adaptive immune response against cancer cells, which in turn have evolved sophisticated cellular defense mechanisms to withstand CTL attack. Herein we provide a critical review of the pertinent literature on early and late attack/defense events taking place at the CTL/target cell lytic synapse. We examine the earliest steps of CTL-mediated cytotoxicity (“the poison arrows”) elicited within seconds of CTL/target cell encounter, which face commensurately rapid synaptic repair mechanisms on the tumor cell side, providing the first formidable barrier to CTL attack. We examine how breach of this first defensive barrier unleashes the inextinguishable “Greek fire” in the form of granzymes whose broad cytotoxic potential is linked to activation of cell death executioners, injury of vital organelles, and destruction of intracellular homeostasis. Herein tumor cells deploy slower but no less sophisticated defensive mechanisms in the form of enhanced autophagy, increased reparative capacity, and dysregulation of cell death pathways. We discuss how the newly discovered supra-molecular attack particles (SMAPs, the “scorpion bombs”), seek to overcome the robust defensive mechanisms that confer tumor cell resistance. Finally, we discuss the implications of the aforementioned attack/defense mechanisms on the induction of regulated cell death (RCD), and how different contemporary RCD modalities (including apoptosis, pyroptosis, and ferroptosis) may have profound implications for immunotherapy. Thus, we propose that understanding and targeting multiple steps of the attack/defense process will be instrumental to enhance the efficacy of CTL anti-tumor activity and meet the outstanding challenges in clinical immunotherapy.

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Actin remodeling and vesicular trafficking at the tumor cell side of the immunological synapse direct evasion from cytotoxic lymphocytes

Cited by 11 publications

References 215 publications

Extracellular vesicles and microvilli in the immune synapse

Extracellular vesicles and microvilli in the immune synapse

An integrated workflow for phosphopeptide identification in natural killer cells (NK-92MI) and their targets (MDA-MB-231) during immunological synapse formation

Greek Fire, Poison Arrows, and Scorpion Bombs: How Tumor Cells Defend Against the Siege Weapons of Cytotoxic T Lymphocytes

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