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.
Subject(s)
B7-H1 Antigen , Carcinoma, Squamous Cell , Cell Plasticity , Epithelial-Mesenchymal Transition , Immune Checkpoint Inhibitors , Immunotherapy , Skin Neoplasms , Animals , Skin Neoplasms/immunology , Skin Neoplasms/pathology , Skin Neoplasms/therapy , Skin Neoplasms/drug therapy , Carcinoma, Squamous Cell/immunology , Carcinoma, Squamous Cell/therapy , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/drug therapy , Mice , Humans , B7-H1 Antigen/metabolism , B7-H1 Antigen/antagonists & inhibitors , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , Male , Immunotherapy/methods , Epithelial-Mesenchymal Transition/immunology , Cell Plasticity/drug effects , Cell Line, Tumor , Programmed Cell Death 1 Receptor/metabolism , Programmed Cell Death 1 Receptor/antagonists & inhibitors , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/metabolism , CTLA-4 Antigen/immunology , Receptors, Virus/metabolism , Receptors, Virus/genetics , B7-1 Antigen/metabolism , Receptors, Immunologic/metabolismABSTRACT
Most tumors exhibit intra-tumor heterogeneity, which is associated with disease progression and an impaired response to therapy. Cancer cell plasticity has been proposed as being an important mechanism that, along with genetic and epigenetic alterations, promotes cancer cell diversity and contributes to intra-tumor heterogeneity. Plasticity endows cancer cells with the capacity to shift dynamically between a differentiated state, with limited tumorigenic potential, and an undifferentiated or cancer stem-like cell (CSC) state, which is responsible for long-term tumor growth. In addition, it confers the ability to transit into distinct CSC states with different competence to invade, disseminate and seed metastasis. Cancer cell plasticity has been linked to the epithelial-to-mesenchymal transition program and relies not only on cell-autonomous mechanisms, but also on signals provided by the tumor microenvironment and/or induced in response to therapy. We provide an overview of the dynamic transition for cancer cell states, the mechanisms governing cell plasticity and their impact on tumor progression, metastasis and therapy response. Understanding the mechanisms involved in cancer cell plasticity will provide insights for establishing new therapeutic interventions.
