PMID- 34078123 OWN - NLM STAT- MEDLINE DCOM- 20220325 LR - 20221003 IS - 1557-9077 (Electronic) IS - 1050-7256 (Print) IS - 1050-7256 (Linking) VI - 31 IP - 10 DP - 2021 Oct TI - CSPG4 Is a Potential Therapeutic Target in Anaplastic Thyroid Cancer. PG - 1481-1493 LID - 10.1089/thy.2021.0067 [doi] AB - Background: Anaplastic thyroid cancer (ATC) is a rare cancer with poor prognosis and few treatment options. The objective of this study was to investigate new immune-associated therapeutic targets by identifying ATC-derived, human leukocyte antigen (HLA) class II-presenting peptides. One protein that generated multiple peptides in ATC was chondroitin sulfate-proteoglycan-4 (CSPG4), a transmembrane proteoglycan with increased expression in multiple aggressive cancers, but not yet investigated in ATC. Methods: We applied autologous peripheral blood T cells to ATC patient-derived xenografted mice to examine whether ATC induces a tumor-specific T cell response. We then identified peptide antigens eluted from the HLA-DQ complex in ATC patient-derived cells using mass spectrometry, detecting abundant CSPG4-derived peptides specific to the ATC sample. Next, we analyzed the surface expression level of CSPG4 in thyroid cancer cell lines and primary cell culture using flow cytometry. In addition, we used immunohistochemistry to compare the expression level and localization of the CSPG4 protein in ATC, papillary thyroid cancer, and normal thyroid tissue. We then investigated the correlation between CSPG4 expression and clinicopathological features of patients with thyroid cancer. Results: We found that ATC tissue had a high level of HLA-DQ expression and that the patient's CD4(+) T cells showed activation when exposed to ATC. By eluting the HLA-DQ complex of ATC tissue, we found that CSPG4 generated one of the most abundant and specific peptides. CSPG4 expression at the cell surface of thyroid cancer was also significantly high when determined by flow cytometry, with the majority of ATC cell lines exhibiting approximately 10-fold higher mean fluorescence intensity. Furthermore, most ATC patient cases expressed CSPG4 in the cytoplasm or membrane of the tumor cells. CSPG4 expression was correlated with tumor size, extrathyroidal extension, and intercellular adhesion molecule-1 (ICAM-1) circumferential expression. CSPG4 mRNA overexpression was associated with worse overall survival in patients with ATC and poorly differentiated thyroid cancer. Conclusions: CSPG4 expression is significantly elevated in aggressive thyroid cancers, with a strong correlation with a poor prognosis. The vast number of HLA-DQ eluted CSPG4 peptides was identified in ATC, demonstrating the potential of CSPG4 as a novel immunotherapeutic target for ATC. FAU - Egan, Caitlin E AU - Egan CE AD - Department of Surgery, Weill Cornell Medicine, New York, New York, USA. FAU - Stefanova, Dessislava AU - Stefanova D AUID- ORCID: 0000-0003-2460-9235 AD - Department of Surgery, Weill Cornell Medicine, New York, New York, USA. FAU - Ahmed, Adnan AU - Ahmed A AD - Department of Biochemistry, Weill Cornell Medicine, New York, New York, USA. FAU - Raja, Vijay J AU - Raja VJ AD - Department of Biochemistry, Weill Cornell Medicine, New York, New York, USA. FAU - Thiesmeyer, Jessica W AU - Thiesmeyer JW AD - Department of Surgery, Weill Cornell Medicine, New York, New York, USA. FAU - Chen, Kevin J AU - Chen KJ AD - Department of Surgery, Weill Cornell Medicine, New York, New York, USA. FAU - Greenberg, Jacques A AU - Greenberg JA AD - Department of Surgery, Weill Cornell Medicine, New York, New York, USA. FAU - Zhang, Taotao AU - Zhang T AD - Department of Pathology, and Weill Cornell Medicine, New York, New York, USA. FAU - He, Bing AU - He B AD - Department of Pathology, and Weill Cornell Medicine, New York, New York, USA. FAU - Finnerty, Brendan M AU - Finnerty BM AD - Department of Surgery, Weill Cornell Medicine, New York, New York, USA. FAU - Zarnegar, Rasa AU - Zarnegar R AUID- ORCID: 0000-0003-2548-5764 AD - Department of Surgery, Weill Cornell Medicine, New York, New York, USA. FAU - Jin, Moonsoo M AU - Jin MM AD - Department of Surgery, Weill Cornell Medicine, New York, New York, USA. AD - Department of Radiology, Weill Cornell Medicine, New York, New York, USA. FAU - Scognamiglio, Theresa AU - Scognamiglio T AD - Department of Pathology, and Weill Cornell Medicine, New York, New York, USA. FAU - Dephoure, Noah AU - Dephoure N AD - Department of Biochemistry, Weill Cornell Medicine, New York, New York, USA. FAU - Fahey, Thomas 3rd AU - Fahey T 3rd AD - Department of Surgery, Weill Cornell Medicine, New York, New York, USA. FAU - Min, Irene M AU - Min IM AUID- ORCID: 0000-0002-1057-4804 AD - Department of Surgery, Weill Cornell Medicine, New York, New York, USA. LA - eng GR - R01 CA217059/CA/NCI NIH HHS/United States GR - R01 CA254035/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210705 PL - United States TA - Thyroid JT - Thyroid : official journal of the American Thyroid Association JID - 9104317 RN - 0 (CSPG4 protein, human) RN - 0 (Chondroitin Sulfate Proteoglycans) RN - 0 (HLA-DQ Antigens) RN - 0 (Membrane Proteins) SB - IM MH - Animals MH - CD4-Positive T-Lymphocytes/immunology MH - Cell Line, Tumor MH - Chondroitin Sulfate Proteoglycans/*genetics/*metabolism MH - *Gene Expression MH - *Gene Expression Regulation, Neoplastic MH - HLA-DQ Antigens/genetics/metabolism MH - Humans MH - Immunotherapy/*methods MH - Membrane Proteins/*genetics/*metabolism MH - Mice MH - Mice, Transgenic MH - *Molecular Targeted Therapy MH - Prognosis MH - Thyroid Carcinoma, Anaplastic/*genetics/immunology/*therapy MH - Thyroid Neoplasms/*genetics/immunology/*therapy PMC - PMC8917884 OTO - NOTNLM OT - CSPG4 OT - anaplastic thyroid cancer OT - thyroid cancer COIS- No competing financial interests exist. EDAT- 2021/06/04 06:00 MHDA- 2022/03/26 06:00 PMCR- 2022/10/01 CRDT- 2021/06/03 05:29 PHST- 2021/06/04 06:00 [pubmed] PHST- 2022/03/26 06:00 [medline] PHST- 2021/06/03 05:29 [entrez] PHST- 2022/10/01 00:00 [pmc-release] AID - 10.1089/thy.2021.0067 [pii] AID - 10.1089/thy.2021.0067 [doi] PST - ppublish SO - Thyroid. 2021 Oct;31(10):1481-1493. doi: 10.1089/thy.2021.0067. Epub 2021 Jul 5.