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| 001 | 179147 | ||
| 005 | 20251119102157.0 | ||
| 024 | 7 | _ | |a 10.1136/jitc-2021-003917 |2 doi |
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| 037 | _ | _ | |a DKFZ-2022-00503 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 610 |
| 100 | 1 | _ | |a Prasad, Manu |b 0 |
| 245 | _ | _ | |a MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer. |
| 260 | _ | _ | |a London |c 2022 |b BioMed Central |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1763544104_2172553 |2 PUB:(DE-HGF) |
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| 500 | _ | _ | |a #DKFZ-MOST-Ca204# |
| 520 | _ | _ | |a Although 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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| 650 | _ | 7 | |a Head and neck cancer |2 Other |
| 650 | _ | 7 | |a MEK1/2 |2 Other |
| 650 | _ | 7 | |a anti-PD-1 |2 Other |
| 650 | _ | 7 | |a immunotherapy |2 Other |
| 650 | _ | 7 | |a targeted therapy |2 Other |
| 650 | _ | 7 | |a tumor-immunity |2 Other |
| 650 | _ | 7 | |a tumor-microenvironment |2 Other |
| 700 | 1 | _ | |a Zorea, Jonathan |b 1 |
| 700 | 1 | _ | |a Jagadeeshan, Sankar |b 2 |
| 700 | 1 | _ | |a Shnerb, Avital B |b 3 |
| 700 | 1 | _ | |a Mathukkada, Sooraj |b 4 |
| 700 | 1 | _ | |a Bouaoud, Jebrane |b 5 |
| 700 | 1 | _ | |a Michon, Lucas |b 6 |
| 700 | 1 | _ | |a Novoplansky, Ofra |b 7 |
| 700 | 1 | _ | |a Badarni, Mai |b 8 |
| 700 | 1 | _ | |a Cohen, Limor |b 9 |
| 700 | 1 | _ | |a Yegodayev, Ksenia M |b 10 |
| 700 | 1 | _ | |a Tzadok, Sapir |b 11 |
| 700 | 1 | _ | |a Rotblat, Barak |b 12 |
| 700 | 1 | _ | |a Brezina, Libor |b 13 |
| 700 | 1 | _ | |a Mock, Andreas |0 P:(DE-He78)8f7c3bc1451193551c2458d93222536a |b 14 |u dkfz |
| 700 | 1 | _ | |a Karabajakian, Andy |b 15 |
| 700 | 1 | _ | |a Fayette, Jérôme |b 16 |
| 700 | 1 | _ | |a Cohen, Idan |b 17 |
| 700 | 1 | _ | |a Cooks, Tomer |b 18 |
| 700 | 1 | _ | |a Allon, Irit |b 19 |
| 700 | 1 | _ | |a Dimitstein, Orr |b 20 |
| 700 | 1 | _ | |a Joshua, Benzion |b 21 |
| 700 | 1 | _ | |a Kong, Dexin |b 22 |
| 700 | 1 | _ | |a Voronov, Elena |b 23 |
| 700 | 1 | _ | |a Scaltriti, Maurizio |b 24 |
| 700 | 1 | _ | |a Carmi, Yaron |b 25 |
| 700 | 1 | _ | |a Conde-Lopez, Cristina |0 P:(DE-HGF)0 |b 26 |
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| 700 | 1 | _ | |a Morris, Luc G T |b 29 |
| 700 | 1 | _ | |a Saintigny, Pierre |0 0000-0002-8090-9323 |b 30 |
| 700 | 1 | _ | |a Elkabets, Moshe |0 0000-0003-3634-9098 |b 31 |
| 773 | _ | _ | |a 10.1136/jitc-2021-003917 |g Vol. 10, no. 3, p. e003917 - |0 PERI:(DE-600)2719863-7 |n 3 |p e003917 |t Journal for ImmunoTherapy of Cancer |v 10 |y 2022 |x 2051-1426 |
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