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L.L.-S. received an IDIBELL Fellowship and an EMBO Short-Term Fellowship (number 7192); M.L.-C. was supported by the FI program (2019FI_B_00265) of the Secretariat for Universities and Research of the Department of Business and Knowledge of the Government of Catalonia, with the support of the European Social Fund (ESF) "ESF, Investing in your future"; V.d.S.-D. was funded by a Spanish Ministry of Science and Innovation Fellowship. The research of P.M.'s group is supported by the Spanish Ministry of Economy and Competitiveness MINECO (SAF2017-84976R and PID2020-113495RB-I00; co-funded by the FEDER funds/European Regional Development Fund (ERDF) - A way to build Europe), Fundacio Vallformosa and GESCO Family, and by the Catalan Department of Health (CERCA, Generalitat de Catalunya, 2017SGR595, 2021 SGR00769). J.M.-L. and P.M. acknowledge funding from Beca GEM (Grupo Espanol Multidisciplinar de Melanoma). We also thank the patients who enrolled in this study for their participation; the Tumor Biobank of the Bellvitge University Hospital and the IdiPAZ Biobank for their help collecting patients' tumor specimens; and the staff at the IDIBELL biostatistics, optical microscopy, and animal facilities, and at the UB/PCB flow cytometry facility for assistance. Figures 1c, 3a and 4a were created with BioRender.com, released under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International license.

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Cancer cell plasticity defines response to immunotherapy in cutaneous squamous cell carcinoma

Publicated to:Nature Communications. 15 (1): 5352- - 2024-06-24 15(1), DOI: 10.1038/s41467-024-49718-8

Authors: Lorenzo-Sanz, Laura; Lopez-Cerda, Marta; da Silva-Diz, Victoria; Artes, Marta H; Llop, Sandra; Penin, Rosa M; Bermejo, Josep Oriol; Gonzalez-Suarez, Eva; Esteller, Manel; Vinals, Francesc; Espinosa, Enrique; Oliva, Marc; Piulats, Josep M; Martin-Liberal, Juan; Munoz, Purificacion

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Abstract

Immune checkpoint blockade (ICB) approaches have changed the therapeutic landscape for many tumor types. However, half of cutaneous squamous cell carcinoma (cSCC) patients remain unresponsive or develop resistance. Here, we show that, during cSCC progression in male mice, cancer cells acquire epithelial/mesenchymal plasticity and change their immune checkpoint (IC) ligand profile according to their features, dictating the IC pathways involved in immune evasion. Epithelial cancer cells, through the PD-1/PD-L1 pathway, and mesenchymal cancer cells, through the CTLA-4/CD80 and TIGIT/CD155 pathways, differentially block antitumor immune responses and determine the response to ICB therapies. Accordingly, the anti-PD-L1/TIGIT combination is the most effective strategy for blocking the growth of cSCCs that contain both epithelial and mesenchymal cancer cells. The expression of E-cadherin/Vimentin/CD80/CD155 proteins in cSCC, HNSCC and melanoma patient samples predicts response to anti-PD-1/PD-L1 therapy. Collectively, our findings indicate that the selection of ICB therapies should take into account the epithelial/mesenchymal features of cancer cells. Immune surveillance is critical to prevent the development and progression of cutaneous squamous cell carcinoma (cSCC). Here, the authors show that epithelial-mesenchymal plasticity in cancer cells is associated with changes in their immune checkpoint ligand profile during mouse cSCC progression, which dictates differential responses to immune checkpoint blockade.

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