Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Nat Commun ; 15(1): 5352, 2024 Jun 24.
Article in English | MEDLINE | ID: mdl-38914547

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/metabolism
2.
Clin Cancer Res ; 27(5): 1491-1504, 2021 03 01.
Article in English | MEDLINE | ID: mdl-33262138

ABSTRACT

PURPOSE: Recurrent and/or metastatic unresectable cutaneous squamous cell carcinomas (cSCCs) are treated with chemotherapy or radiotherapy, but have poor clinical responses. A limited response (up to 45% of cases) to EGFR-targeted therapies was observed in clinical trials with patients with advanced and metastatic cSCC. Here, we analyze the molecular traits underlying the response to EGFR inhibitors, and the mechanisms responsible for cSCC resistance to EGFR-targeted therapy. EXPERIMENTAL DESIGN: We generated primary cell cultures and patient cSCC-derived xenografts (cSCC-PDXs) that recapitulate the histopathologic and molecular features of patient tumors. Response to gefitinib treatment was tested and gefitinib-resistant (GefR) cSCC-PDXs were developed. RNA sequence analysis was performed in matched untreated and GefR cSCC-PDXs to determine the mechanisms driving gefitinib resistance. RESULTS: cSCCs conserving epithelial traits exhibited strong activation of EGFR signaling, which promoted tumor cell proliferation, in contrast to mesenchymal-like cSCCs. Gefitinib treatment strongly blocked epithelial-like cSCC-PDX growth in the absence of EGFR and RAS mutations, whereas tumors carrying the E545K PIK3CA-activating mutation were resistant to treatment. A subset of initially responding tumors acquired resistance after long-term treatment, which was induced by the bypass from EGFR to FGFR signaling to allow tumor cell proliferation and survival upon gefitinib treatment. Pharmacologic inhibition of FGFR signaling overcame resistance to EGFR inhibitor, even in PIK3CA-mutated tumors. CONCLUSIONS: EGFR-targeted therapy may be appropriate for treating many epithelial-like cSCCs without PIK3CA-activating mutations. Combined EGFR- and FGFR-targeted therapy may be used to treat cSCCs that show intrinsic or acquired resistance to EGFR inhibitors.


Subject(s)
Drug Resistance, Neoplasm , Gefitinib/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Neoplasms, Glandular and Epithelial/drug therapy , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Skin Neoplasms/drug therapy , Animals , Apoptosis , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Cell Proliferation , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Humans , Male , Mice , Mice, Inbred NOD , Mice, SCID , Mutation , Neoplasms, Glandular and Epithelial/metabolism , Neoplasms, Glandular and Epithelial/pathology , Protein Kinase Inhibitors/pharmacology , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
SELECTION OF CITATIONS
SEARCH DETAIL
...