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000304484 1001_ $$aWilgenbus, Petra$$b0
000304484 245__ $$aCoagulation proteases modulate nucleic acid uptake and cGAS-STING-IFN induction in the tumor microenvironment.
000304484 260__ $$aAnn Arbor, Michigan$$bJCI Insight$$c2025
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000304484 520__ $$aMalignancies increase the risk for thrombosis and metastasis dependent on complex interactions of innate immune cells, platelets, and the coagulation system. Immunosuppressive functions of platelets and macrophage-derived coagulation factors in the tumor microenvironment (TME) drive tumor growth. Here, we show that patients with malignancies and tumor-bearing mice have increased levels of coagulation factor (F) X-expressing circulating monocytes engaged in platelet aggregate formation. This interaction and resulting thrombin generation on platelets interferes with monocyte differentiation and antigen uptake of antigen-presenting cells (APCs). Myeloid cell-specific deletion of FX or abrogated FXa signaling via protease activated receptor 2 (PAR2) averts the suppressive activity of platelets on tumor cell debris uptake and promotes the immune stimulatory activity of APCs in the TME. Myeloid cell FXa-PAR2 signaling deficiency specifically enhances activation of the cGAS-STING-IFN-I pathway with a resulting expansion of antigen experienced progenitor exhausted CD8+ T cells. Pharmacological blockade of FXa with direct oral anticoagulants expands T cell priming-competent immune cells in the TME and synergizes with the reactivation of exhausted CD8+ T cells by immune checkpoint inhibitors for improved antitumor responses. These data provide mechanistic insights into the emerging clinical evidence demonstrating the translational potential of FXa inhibition to synergize with immunotherapy.
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000304484 650_7 $$2Other$$aCancer immunotherapy
000304484 650_7 $$2Other$$aCoagulation
000304484 650_7 $$2Other$$aImmunology
000304484 650_7 $$2Other$$aOncology
000304484 650_7 $$2Other$$aPlatelets
000304484 650_7 $$2Other$$aVascular biology
000304484 650_7 $$2NLM Chemicals$$aMembrane Proteins
000304484 650_7 $$0EC 2.7.7.-$$2NLM Chemicals$$aNucleotidyltransferases
000304484 650_7 $$2NLM Chemicals$$aSTING1 protein, human
000304484 650_7 $$0EC 2.7.7.-$$2NLM Chemicals$$acGAS protein, human
000304484 650_7 $$2NLM Chemicals$$aSting1 protein, mouse
000304484 650_7 $$0EC 3.4.21.6$$2NLM Chemicals$$aFactor Xa
000304484 650_7 $$2NLM Chemicals$$aReceptor, PAR-2
000304484 650_7 $$0EC 2.7.7.-$$2NLM Chemicals$$acGAS protein, mouse
000304484 650_2 $$2MeSH$$aTumor Microenvironment: immunology
000304484 650_2 $$2MeSH$$aAnimals
000304484 650_2 $$2MeSH$$aHumans
000304484 650_2 $$2MeSH$$aMice
000304484 650_2 $$2MeSH$$aMembrane Proteins: metabolism
000304484 650_2 $$2MeSH$$aNucleotidyltransferases: metabolism
000304484 650_2 $$2MeSH$$aNeoplasms: immunology
000304484 650_2 $$2MeSH$$aNeoplasms: pathology
000304484 650_2 $$2MeSH$$aSignal Transduction
000304484 650_2 $$2MeSH$$aBlood Platelets: metabolism
000304484 650_2 $$2MeSH$$aBlood Platelets: immunology
000304484 650_2 $$2MeSH$$aFactor Xa: metabolism
000304484 650_2 $$2MeSH$$aFactor Xa: genetics
000304484 650_2 $$2MeSH$$aFemale
000304484 650_2 $$2MeSH$$aReceptor, PAR-2: metabolism
000304484 650_2 $$2MeSH$$aReceptor, PAR-2: genetics
000304484 650_2 $$2MeSH$$aCD8-Positive T-Lymphocytes: immunology
000304484 650_2 $$2MeSH$$aMice, Inbred C57BL
000304484 650_2 $$2MeSH$$aMonocytes: metabolism
000304484 650_2 $$2MeSH$$aMonocytes: immunology
000304484 650_2 $$2MeSH$$aAntigen-Presenting Cells: immunology
000304484 650_2 $$2MeSH$$aMale
000304484 7001_ $$aPott, Jennifer$$b1
000304484 7001_ $$aPagel, Sven$$b2
000304484 7001_ $$aWitzler, Claudius$$b3
000304484 7001_ $$aRoyce, Jennifer$$b4
000304484 7001_ $$aMarini, Federico$$b5
000304484 7001_ $$aReyda, Sabine$$b6
000304484 7001_ $$aMadhusudhan, Thati$$b7
000304484 7001_ $$0P:(DE-HGF)0$$aKindler, Thomas$$b8
000304484 7001_ $$aHausen, Anne$$b9
000304484 7001_ $$aGaida, Matthias M$$b10
000304484 7001_ $$aWeiler, Hartmut$$b11
000304484 7001_ $$aRuf, Wolfram$$b12
000304484 7001_ $$aGraf, Claudine$$b13
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