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

• Published in: Nature communications Vol. 15; no. 1; pp. 5352 - 18
• Main Authors: Lorenzo-Sanz, Laura, Lopez-Cerda, Marta, da Silva-Diz, Victoria, Artés, Marta H, Llop, Sandra, Penin, Rosa M, Bermejo, Josep Oriol, Gonzalez-Suarez, Eva, Esteller, Manel, Viñals, Francesc, Espinosa, Enrique, Oliva, Marc, Piulats, Josep M, Martin-Liberal, Juan, Muñoz, Purificación
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 24.06.2024; Nature Portfolio
• Subjects: Animals; Antitumor activity; B7-1 Antigen - metabolism; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - metabolism; Blocking; Cancer; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - immunology; Carcinoma, Squamous Cell - pathology; Carcinoma, Squamous Cell - therapy; CD80 antigen; Cell Line, Tumor; Cell Plasticity - drug effects; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 Antigen - immunology; CTLA-4 Antigen - metabolism; CTLA-4 protein; E-cadherin; Epithelial-Mesenchymal Transition - immunology; Head and neck carcinoma; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immune response; Immunosurveillance; Immunotherapy; Immunotherapy - methods; Ligands; Male; Melanoma; Mice; PD-1 protein; PD-L1 protein; Plastic properties; Plasticity; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - metabolism; Receptors, Immunologic - metabolism; Receptors, Virus - genetics; Receptors, Virus - metabolism; Skin Neoplasms - drug therapy; Skin Neoplasms - immunology; Skin Neoplasms - pathology; Skin Neoplasms - therapy; Squamous cell carcinoma; Vimentin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49718-8

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.