IFNγ-induced changes in mitochondrial metabolism as a novel strategy for pancreatic cancer therapy

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00023001%3A_____%2F23%3A00084321" target="_blank" >RIV/00023001:_____/23:00084321 - isvavai.cz</a>

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

IFNγ-induced changes in mitochondrial metabolism as a novel strategy for pancreatic cancer therapy

Popis výsledku v původním jazyce

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease for which there is currently no effective therapy. The PDAC tumours show repression of the anticancer immunity in their microenvironment. Immune checkpoint inhibitors aim to stimulate anticancer immune defence via activation of T-lymphocytes producing IFNγ, which was shown to induce cell death in malignant cells. Despite the well-established mechanism of IFNγ induced cell death, its effect on mitochondria and cellular metabolism remains elusive. Our goal was to study the role of IFNγ in regulation of mitochondrial biogenesis and its contribution to cell death.Methods: Metabolic parameters were evaluated using flow-cytometry, confocal microscopy, and Oxygraph2k/Oroboros instrument. For in vivo studies, orthotopic and subcutaneously model of PDAC was engaged. Human and murine cell lines were grafted into NSG or C57BL/6 mice respectively. Treatment was applied by intraperitoneal injection.Results: We show that IFNγ and IFNγ-producing immunotherapy represented by anti-PD-1 immune checkpoint inhibitor blocks aerobic glycolysis, prevents upregulation of glucose transporter and lactate secretion. Further, IFNγ regulates mitochondrial function in PDAC cells via increased autophagy of damaged mitochondria. These changes in metabolism make the pancreatic tumours more susceptible to OXPHOS inhibition by MitoTam, a potentially new anticancer agent that selectively targets highly polarized mitochondria of malignant cell, where induces electrochemical imbalance resulting in cell death. This combined therapy showed stabilization or rejection of tumours and significantly prolonged survival in all tested animals compared to immunotherapy or MitoTam alone.Conclusion: IFNγ produced during immunotherapy regulates mitochondrial biogenesis in PDAC with metabolic shift to oxidative phosphorylation and improves tumour microenvironment. Our study therefore suggests a novel promising strategy for treatment of pancreatic cancer by simultaneous targeting of mitochondrial metabolism and immune checkpoints.

Název v anglickém jazyce

IFNγ-induced changes in mitochondrial metabolism as a novel strategy for pancreatic cancer therapy

Popis výsledku anglicky

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease for which there is currently no effective therapy. The PDAC tumours show repression of the anticancer immunity in their microenvironment. Immune checkpoint inhibitors aim to stimulate anticancer immune defence via activation of T-lymphocytes producing IFNγ, which was shown to induce cell death in malignant cells. Despite the well-established mechanism of IFNγ induced cell death, its effect on mitochondria and cellular metabolism remains elusive. Our goal was to study the role of IFNγ in regulation of mitochondrial biogenesis and its contribution to cell death.Methods: Metabolic parameters were evaluated using flow-cytometry, confocal microscopy, and Oxygraph2k/Oroboros instrument. For in vivo studies, orthotopic and subcutaneously model of PDAC was engaged. Human and murine cell lines were grafted into NSG or C57BL/6 mice respectively. Treatment was applied by intraperitoneal injection.Results: We show that IFNγ and IFNγ-producing immunotherapy represented by anti-PD-1 immune checkpoint inhibitor blocks aerobic glycolysis, prevents upregulation of glucose transporter and lactate secretion. Further, IFNγ regulates mitochondrial function in PDAC cells via increased autophagy of damaged mitochondria. These changes in metabolism make the pancreatic tumours more susceptible to OXPHOS inhibition by MitoTam, a potentially new anticancer agent that selectively targets highly polarized mitochondria of malignant cell, where induces electrochemical imbalance resulting in cell death. This combined therapy showed stabilization or rejection of tumours and significantly prolonged survival in all tested animals compared to immunotherapy or MitoTam alone.Conclusion: IFNγ produced during immunotherapy regulates mitochondrial biogenesis in PDAC with metabolic shift to oxidative phosphorylation and improves tumour microenvironment. Our study therefore suggests a novel promising strategy for treatment of pancreatic cancer by simultaneous targeting of mitochondrial metabolism and immune checkpoints.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30204 - Oncology

Projekt

<a href="/cs/project/LX22NPO5104" target="_blank" >LX22NPO5104: Národní institut pro výzkum metabolických a kardiovaskulárních onemocnění</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2023

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů