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

Laura Lorenzo-Sanz (), Marta Lopez-Cerda, Victoria da Silva-Diz, Marta H. Artés, Sandra Llop, Rosa M. Penin, Josep Oriol Bermejo, Eva Gonzalez-Suarez, Manel Esteller, Francesc Viñals, Enrique Espinosa, Marc Oliva, Josep M. Piulats, Juan Martin-Liberal and Purificación Muñoz ()
Additional contact information
Laura Lorenzo-Sanz: Bellvitge Biomedical Research Institute (IDIBELL)
Marta Lopez-Cerda: Bellvitge Biomedical Research Institute (IDIBELL)
Victoria da Silva-Diz: Bellvitge Biomedical Research Institute (IDIBELL)
Marta H. Artés: Bellvitge Biomedical Research Institute (IDIBELL)
Sandra Llop: Catalan Institute of Oncology (ICO)
Rosa M. Penin: Bellvitge University Hospital/IDIBELL
Josep Oriol Bermejo: Bellvitge University Hospital/IDIBELL
Eva Gonzalez-Suarez: Bellvitge Biomedical Research Institute (IDIBELL)
Manel Esteller: Josep Carreras Leukaemia Research Institute (IJC)
Francesc Viñals: Bellvitge Biomedical Research Institute (IDIBELL)
Enrique Espinosa: ISCIII
Marc Oliva: Catalan Institute of Oncology (ICO)
Josep M. Piulats: Bellvitge Biomedical Research Institute (IDIBELL)
Juan Martin-Liberal: Catalan Institute of Oncology (ICO)
Purificación Muñoz: Bellvitge Biomedical Research Institute (IDIBELL)

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49718-8

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