New insights into cancer's exploitation of platelets

Francisco, Brenton J; Palumbo, Joseph S.

doi:10.1111/jth.14624

Cited by 3 publications

(4 citation statements)

References 47 publications

(107 reference statements)

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“…Several mechanisms have been proposed for coagulation cascade-mediated NK cell inhibition (Francisco & Palumbo, 2019), including that platelet-tumor aggregates physically protect tumor cells from NK cells (Cluxton et al, 2019, Nierodzik & Karpatkin, 2006. However, we rarely observed microthrombi around the disseminated tumor cells, even when a microthrombus was easily induced by laser ablation in the vicinity of the tumor cell (Figure 6-figure supplement 2 and Figure 6-video 1).…”

Section: Thrombin-mediated Shedding Of Necl5 Correlates Evasion Of Nk...mentioning

confidence: 71%

“…The ratio of extracellular mScarlet versus intracellular mNeonGreen was markedly reduced in 24 hrs, indicating loss of extracellular domain, possibly by cleavage or shedding (Figure 6D,6E). A clue to the mechanism of this Necl5 loss came from evidence that inhibition of serine proteases in the coagulation cascade have anti-tumor effects in rodent models and human patients (Francisco & Palumbo, 2019, Nierodzik & Karpatkin, 2006. Warfarin, an anti-vitamin K drug, potently accelerated the acute elimination of tumor cells (Figure 6F).…”

Section: Thrombin-mediated Shedding Of Necl5 Correlates Evasion Of Nk...mentioning

confidence: 99%

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Functional visualization of NK cell-mediated killing of metastatic single tumor cells

Ichise

Tsukamoto

Hirashima

et al. 2022

eLife

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Natural killer (NK) cells lyse invading tumor cells to limit metastatic growth in the lung, but how some cancers evade this host protective mechanism to establish a growing lesion is unknown. Here we have combined ultra-sensitive bioluminescence imaging with intravital two-photon microscopy involving genetically-encoded biosensors to examine this question. NK cells eliminated disseminated tumor cells from the lung within 24 hrs of arrival, but not thereafter. Intravital dynamic imaging revealed that 50% of NK-tumor cell encounters lead to tumor cell death in the first 4 hrs after tumor cell arrival, but after 24 hrs of arrival, nearly 100% of the interactions result in the survival of the tumor cell. During this 24 hrs period, the probability of ERK activation in NK cells upon encountering the tumor cells was decreased from 68% to 8%, which correlated with the loss of the activating ligand CD155/PVR/Necl5 from the tumor cell surface. Thus, by quantitatively visualizing the NK-tumor cell interaction at the early stage of metastasis, we have revealed the crucial parameters of NK cell immune surveillance in the lung.

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Section: Thrombin-mediated Shedding Of Necl5 Correlates Evasion Of Nk...mentioning

confidence: 71%

Section: Thrombin-mediated Shedding Of Necl5 Correlates Evasion Of Nk...mentioning

confidence: 99%

Functional visualization of NK cell-mediated killing of metastatic single tumor cells

Ichise

Tsukamoto

Hirashima

et al. 2022

eLife

View full text Add to dashboard Cite

show abstract

“…The ratio of extracellular mScarlet versus intracellular mNeonGreen was markedly reduced in 24 hrs, indicating loss of extracellular domain, possibly by cleavage or shedding ( Figure 6D, 6E). A clue to the mechanism of this Necl-5 loss came from evidence that inhibition of serine proteases in the coagulation cascade have anti-tumor effects in rodent models and human patients (Francisco and Palumbo, 2019;Nierodzik and Karpatkin, 2006). Warfarin, an anti-vitamin K drug potently accelerated the acute elimination of tumor cells ( Figure 6F).…”

Section: Thrombin-mediated Shedding Of Necl-5 Causes Evasion Of Nk Cementioning

confidence: 99%

“…In agreement with these functional results, thrombin cleaved off the extracellular domain of Necl-5 from tumor cells in vitro ( Figure 6I). Several mechanisms have been proposed for coagulation cascade-mediated NK cell inhibition (Francisco and Palumbo, 2019), including that platelet-tumor aggregates physically protect tumor cells from NK cells (Cluxton et al, 2019;Nierodzik and Karpatkin, 2006). However, we rarely observed microthrombi around the disseminated tumor cells, even when a microthrombus was easily induced by laser ablation in the vicinity of the tumor cell ( Figure S9 and Supplementary Video 5).…”

Section: Thrombin-mediated Shedding Of Necl-5 Causes Evasion Of Nk Cementioning

confidence: 99%

Metastatic Single Tumor Cells Evade NK Cell-mediated Killing by Thrombin-mediated Loss of the Activating Ligand CD155/PVR/Necl-5

Ichise

Tsukamoto

Hirashima

et al. 2021

Preprint

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Natural killer (NK) cells lyse invading tumor cells to limit metastatic growth in the lung, but how some cancers evade this host protective mechanism to establish a growing lesion is not known. Here we have combined ultra-sensitive bioluminescence whole body imaging with intravital two-photon microscopy involving genetically-encoded biosensors to examine this question. NK cells eliminated disseminated tumor cells from the lung within 24 hrs of arrival, but not thereafter. Intravital dynamic imaging revealed that a disseminated tumor cell in a pulmonary capillary interacts with an NK cell every 2 hrs on average. In the first 4 hrs after tumor cell arrival, 50% of such encounters lead to tumor cell death but after 24 hrs of arrival, nearly 100% of the interactions result in the survival of the tumor cell. This evasion of NK cell surveillance is mediated by thrombin-dependent loss of cell surface CD155/PVR/Necl-5, a ligand for the NK cell activating receptor DNAM-1. This loss prevents the NK cell signaling needed for effective killing of tumor targets. By quantitatively visualizing the evasion of NK cell surveillance, we have uncovered a molecular mechanism for cancer evasion and provided an explanation for the anti-metastatic effect of anticoagulants.SUMMARYIntravital functional two-photon microscopy reveals that metastatic tumor cells lodged in pulmonary capillaries acquire resistance to patrolling NK cells. Protease-mediated loss of the activating ligand CD155/PVR/Necl-5 on tumor cells prevents NK cells from ERK activation and tumor cell killing.

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Intravital Imaging Identifies the VEGF–TXA2 Axis as a Critical Promoter of PGE2 Secretion from Tumor Cells and Immune Evasion

et al. 2021

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Prostaglandin E2 (PGE2) promotes tumor progression through evasion of antitumor immunity. In stark contrast to cyclooxygenase-dependent production of PGE2, little is known whether PGE2 secretion is regulated within tumor tissues. Here, we show that VEGF-dependent release of thromboxane A2 (TXA2) triggers Ca2+ transients in tumor cells, culminating in PGE2 secretion and subsequent immune evasion in the early stages of tumorigenesis. Ca2+ transients caused cPLA2 activation and triggered the arachidonic acid cascade. Ca2+ transients were monitored as the surrogate marker of PGE2 secretion. Intravital imaging of BrafV600E mouse melanoma cells revealed that the proportion of cells exhibiting Ca2+ transients is markedly higher in vivo than in vitro. The TXA2 receptor was indispensable for the Ca2+ transients in vivo, high intratumoral PGE2 concentration, and evasion of antitumor immunity. Notably, treatment with a VEGF receptor antagonist and an anti-VEGF antibody rapidly suppressed Ca2+ transients and reduced TXA2 and PGE2 concentrations in tumor tissues. These results identify the VEGF–TXA2 axis as a critical promoter of PGE2-dependent tumor immune evasion, providing a molecular basis underlying the immunomodulatory effect of anti-VEGF therapies. Significance: This study identifies the VEGF–TXA2 axis as a potentially targetable regulator of PGE2 secretion, which provides novel strategies for prevention and treatment of multiple types of malignancies.

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New insights into cancer's exploitation of platelets

Cited by 3 publications

References 47 publications

Functional visualization of NK cell-mediated killing of metastatic single tumor cells

Functional visualization of NK cell-mediated killing of metastatic single tumor cells

Metastatic Single Tumor Cells Evade NK Cell-mediated Killing by Thrombin-mediated Loss of the Activating Ligand CD155/PVR/Necl-5

Intravital Imaging Identifies the VEGF–TXA2 Axis as a Critical Promoter of PGE2 Secretion from Tumor Cells and Immune Evasion

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