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000179147 0247_ $$2doi$$a10.1136/jitc-2021-003917
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000179147 041__ $$aEnglish
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000179147 1001_ $$aPrasad, Manu$$b0
000179147 245__ $$aMEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer.
000179147 260__ $$aLondon$$bBioMed Central$$c2022
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000179147 520__ $$aAlthough the mitogen-activated protein kinases (MAPK) pathway is hyperactive in head and neck cancer (HNC), inhibition of MEK1/2 in HNC patients has not shown clinically meaningful activity. Therefore, we aimed to characterize the effect of MEK1/2 inhibition on the tumor microenvironment (TME) of MAPK-driven HNC, elucidate tumor-host interaction mechanisms facilitating immune escape on treatment, and apply rationale-based therapy combination immunotherapy and MEK1/2 inhibitor to induce tumor clearance.Mouse syngeneic tumors and xenografts experiments were used to analyze tumor growth in vivo. Single-cell cytometry by time of flight, flow cytometry, and tissue stainings were used to profile the TME in response to trametinib (MEK1/2 inhibitor). Co-culture of myeloid-derived suppressor cells (MDSC) with CD8+ T cells was used to measure immune suppression. Overexpression of colony-stimulating factor-1 (CSF-1) in tumor cells was used to show the effect of tumor-derived CSF-1 on sensitivity to trametinib and anti-programmed death- 1 (αPD-1) in mice. In HNC patients, the ratio between CSF-1 and CD8A was measured to test the association with clinical benefit to αPD-1 and αPD-L1 treatment.Using preclinical HNC models, we demonstrated that treatment with trametinib delays HNC initiation and progression by reducing tumor cell proliferation and enhancing the antitumor immunity of CD8+ T cells. Activation of CD8+ T cells by supplementation with αPD-1 antibody eliminated tumors and induced an immune memory in the cured mice. Mechanistically, an early response to trametinib treatment sensitized tumors to αPD-1-supplementation by attenuating the expression of tumor-derived CSF-1, which reduced the abundance of two CSF-1R+CD11c+ MDSC populations in the TME. In contrast, prolonged treatment with trametinib abolished the antitumor activity of αPD-1, because tumor cells undergoing the epithelial to mesenchymal transition in response to trametinib restored CSF-1 expression and recreated an immune-suppressive TME.Our findings provide the rationale for testing the trametinib/αPD-1 combination in HNC and highlight the importance of sensitizing tumors to αPD-1 by using MEK1/2 to interfere with the tumor-host interaction. Moreover, we describe the concept that treatment of cancer with a targeted therapy transiently induces an immune-active microenvironment, and supplementation of immunotherapy during this time further activates the antitumor machinery to cause tumor elimination.
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000179147 650_7 $$2Other$$aHead and neck cancer
000179147 650_7 $$2Other$$aMEK1/2
000179147 650_7 $$2Other$$aanti-PD-1
000179147 650_7 $$2Other$$aimmunotherapy
000179147 650_7 $$2Other$$atargeted therapy
000179147 650_7 $$2Other$$atumor-immunity
000179147 650_7 $$2Other$$atumor-microenvironment
000179147 7001_ $$aZorea, Jonathan$$b1
000179147 7001_ $$aJagadeeshan, Sankar$$b2
000179147 7001_ $$aShnerb, Avital B$$b3
000179147 7001_ $$aMathukkada, Sooraj$$b4
000179147 7001_ $$aBouaoud, Jebrane$$b5
000179147 7001_ $$aMichon, Lucas$$b6
000179147 7001_ $$aNovoplansky, Ofra$$b7
000179147 7001_ $$aBadarni, Mai$$b8
000179147 7001_ $$aCohen, Limor$$b9
000179147 7001_ $$aYegodayev, Ksenia M$$b10
000179147 7001_ $$aTzadok, Sapir$$b11
000179147 7001_ $$aRotblat, Barak$$b12
000179147 7001_ $$aBrezina, Libor$$b13
000179147 7001_ $$0P:(DE-He78)8f7c3bc1451193551c2458d93222536a$$aMock, Andreas$$b14$$udkfz
000179147 7001_ $$aKarabajakian, Andy$$b15
000179147 7001_ $$aFayette, Jérôme$$b16
000179147 7001_ $$aCohen, Idan$$b17
000179147 7001_ $$aCooks, Tomer$$b18
000179147 7001_ $$aAllon, Irit$$b19
000179147 7001_ $$aDimitstein, Orr$$b20
000179147 7001_ $$aJoshua, Benzion$$b21
000179147 7001_ $$aKong, Dexin$$b22
000179147 7001_ $$aVoronov, Elena$$b23
000179147 7001_ $$aScaltriti, Maurizio$$b24
000179147 7001_ $$aCarmi, Yaron$$b25
000179147 7001_ $$0P:(DE-HGF)0$$aConde-Lopez, Cristina$$b26
000179147 7001_ $$0P:(DE-He78)2e5f34f1c58eda4787a14c9dc139ca5f$$aHess, Jochen$$b27$$udkfz
000179147 7001_ $$0P:(DE-He78)f3723bca6eb95009d4c95a7590617b68$$aKurth, Ina$$b28$$udkfz
000179147 7001_ $$aMorris, Luc G T$$b29
000179147 7001_ $$00000-0002-8090-9323$$aSaintigny, Pierre$$b30
000179147 7001_ $$00000-0003-3634-9098$$aElkabets, Moshe$$b31
000179147 773__ $$0PERI:(DE-600)2719863-7$$a10.1136/jitc-2021-003917$$gVol. 10, no. 3, p. e003917 -$$n3$$pe003917$$tJournal for ImmunoTherapy of Cancer$$v10$$x2051-1426$$y2022
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