MAGE-A3 is a Clinically Relevant Target in Undifferentiated Pleomorphic Sarcoma/Myxofibrosarcoma.

Anthony P Conley,John A Livingston,Jason Roszik,Vinod Ravi,Vivek Subbiah,Caitlin D Lowery,Wei-Lien Wang,Christina L Roland,Cassian Yee,Neeta Somaiah,Shreyaskumar Patel,Patrick Hwu,Andrew Futreal,Ali Ali,Davis R Ingram,Jen-Wei Tsai,Alexander J Lazar

doi:10.3390/cancers11050677

Anthony P Conley, John A Livingston + Show 15 more

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https://doi.org/10.3390/cancers11050677

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Journal: Cancers	Publication Date: May 15, 2019
Citations: 21	License type: CC BY 4.0

Affiliation: The University of Texas MD Anderson Cancer Center

Abstract

Melanoma-associated antigen 3 (MAGE-A3) expression is generally restricted to the placenta and germline cells of the testis, but it may also be expressed in sarcoma and other cancers and is associated with poor prognosis. Immunotherapy approaches targeting MAGE-A3 in other cancers have shown mixed results in the clinic, however, use of cancer testis antigens such as MAGE-A3 may have therapeutic value in the treatment of soft tissue sarcomas. Based on the recent success of anti-programmed death-1 (PD-1) therapy in undifferentiated pleomorphic sarcoma, we hypothesize that MAGE-A3-based immunotherapies may also provide benefits in this sarcoma type. We analyzed MAGE-A3 expression of sarcoma subtypes available in the Cancer Genome Atlas and Cancer Cell Line Encyclopedia and show that undifferentiated pleomorphic sarcoma/myxofibrosarcoma (UPS/MFS) expresses this potential target gene. We have identified high protein expression by tissue microarray of 106 UPS cores. We also found that high MAGE-A3 mRNA and protein expression is associated with worse overall survival in UPS/MFS. Furthermore, our results show no human leukocyte antigen (HLA) expression loss and relatively high lymphocyte infiltration by lymphocyte specific protein tyrosine kinase (LCK) marker expression. Based on these results, we propose targeting MAGE-A3 in UPS/MFS by immunotherapy techniques.

Highlights

Melanoma-associated antigen 3 (MAGE-A3) is located on chromosome Xq28 and encodes the MAGE-A3 protein
MAGE-A3 Is Expressed in Multiple Cancers and a Limited Number of Normal Tissues was compared with MAGE-A3 mRNA expression from normal tissues in the Genotype-Tissue
MAGE-A3 mRNA expression was available from thirty-three cancers accessed from The Cancer

Summary

Introduction

Melanoma-associated antigen 3 (MAGE-A3) is located on chromosome Xq28 and encodes the MAGE-A3 protein. As a member of the MAGE gene family, the MAGE-A3 protein is one of several. MAGE proteins capable of binding with and enhancing E3 Really Interesting New Gene (RING). To other cancer-testis antigens, expression of MAGE-A3 is usually restricted to the placenta and germline cells of the testis [2], but frequently overexpressed in multiple tumor types including melanoma [3] and lung cancer [4]. Presence of this antigen has been associated with worse prognosis in colorectal cancer [5], gastric cancer [6], non-small cell lung cancer [7], cutaneous squamous cell carcinoma [8] and diffuse large B-cell lymphoma [9]. An HLA-DPB1*0401-restricted MAGE-A3-specific CD4+ T cell-based adoptive cell therapy was noted to be safe, and objective responses were observed in metastatic cervical cancer, esophageal cancer, urothelial cancer, and in a patient with osteosarcoma [10]

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