TY - JOUR
T1 - SLC45A2
T2 - A melanoma antigen with high tumor selectivity and reduced potential for autoimmune toxicity
AU - Park, Jungsun
AU - Talukder, Amjad H.
AU - Lim, Seon A.
AU - Kim, Kwanghee
AU - Pan, Ke
AU - Melendez, Brenda
AU - Bradley, Sherille D.
AU - Jackson, Kyle R.
AU - Khalili, Jahan S.
AU - Wang, Junmei
AU - Creasy, Caitlin
AU - Pan, Bih Fang
AU - Woodman, Scott E.
AU - Bernatchez, Chantale
AU - Hawke, David
AU - Hwu, Patrick
AU - Lee, Kyung Mi
AU - Roszik, Jason
AU - Lizee, Gregory
AU - Yee, Cassian
N1 - Funding Information:
We thank Dr. Peter P. Lee for kindly providing two HLA A0201-positive melanocytes, and thank the UT-MDACC Proteomics and Metabolomics Facility for their invaluable contributions to the MDACC antigen discovery pipeline. Research supported by a Stand Up To Cancer-Cancer Research Institute Cancer Immunology Translational Research Grant. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. Cassian Yee is a Scholar of the Cancer Prevention Research Institute of Texas (CPRIT). This work was supported by the Cancer Prevention Research Institute of Texas (CPRIT) grant RP130397, The National Institutes of Health (NIH) grant 1S10OD012304-01, National Research Foundation of Korea Grants NRF-2013M3A9D3045719 and NRF-2016M3A9B6948342, and by generous philanthropic contributions to The University of Texas MD Anderson Melanoma Moon Shots Program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2017 AACR.
PY - 2017/8
Y1 - 2017/8
N2 - Cytotoxic T lymphocyte (CTL)–based immunotherapies have had remarkable success at generating objective clinical responses in patients with advanced metastatic melanoma. Although the melanocyte differentiation antigens (MDA) MART-1, PMEL, and tyrosinase were among the first melanoma tumor-associated antigens identified and targeted with immunotherapy, expression within normal melanocytes of the eye and inner ear can elicit serious autoimmune side effects, thus limiting their clinical potential as CTL targets. Using a tandem mass spectrometry (MS) approach to analyze the immunopep-tidomes of 55 melanoma patient–derived cell lines, we identified a number of shared HLA class I–bound peptides derived from the melanocyte-specific transporter protein SLC45A2. Antigen-specific CTLs generated against HLA-A0201- and HLA-A2402–restricted SLC45A2 peptides effectively killed a majority of HLA-matched cutaneous, uveal, and mucosal melanoma cell lines tested (18/25). CTLs specific for SLC45A2 showed significantly reduced recognition of HLA-matched primary melanocytes that were, conversely, robustly killed by MART1- and PMEL-specific T cells. Transcriptome analysis revealed that SLC45A2 mRNA expression in normal melanocytes was less than 2% that of other MDAs, therefore providing a more favorable melanoma-to-melanocyte expression ratio. Expression of SLC45A2 and CTL sensitivity could be further upregulated in BRAF(V600E)-mutant melanoma cells upon treatment with BRAF or MEK inhibitors, similarly to other MDAs. Taken together, our study demonstrates the feasibility of using tandem MS as a means of discovering shared immunogenic tumor-associated epitopes and identifies SLC45A2 as a promising immunotherapeutic target for melanoma with high tumor selectivity and reduced potential for autoimmune toxicity.
AB - Cytotoxic T lymphocyte (CTL)–based immunotherapies have had remarkable success at generating objective clinical responses in patients with advanced metastatic melanoma. Although the melanocyte differentiation antigens (MDA) MART-1, PMEL, and tyrosinase were among the first melanoma tumor-associated antigens identified and targeted with immunotherapy, expression within normal melanocytes of the eye and inner ear can elicit serious autoimmune side effects, thus limiting their clinical potential as CTL targets. Using a tandem mass spectrometry (MS) approach to analyze the immunopep-tidomes of 55 melanoma patient–derived cell lines, we identified a number of shared HLA class I–bound peptides derived from the melanocyte-specific transporter protein SLC45A2. Antigen-specific CTLs generated against HLA-A0201- and HLA-A2402–restricted SLC45A2 peptides effectively killed a majority of HLA-matched cutaneous, uveal, and mucosal melanoma cell lines tested (18/25). CTLs specific for SLC45A2 showed significantly reduced recognition of HLA-matched primary melanocytes that were, conversely, robustly killed by MART1- and PMEL-specific T cells. Transcriptome analysis revealed that SLC45A2 mRNA expression in normal melanocytes was less than 2% that of other MDAs, therefore providing a more favorable melanoma-to-melanocyte expression ratio. Expression of SLC45A2 and CTL sensitivity could be further upregulated in BRAF(V600E)-mutant melanoma cells upon treatment with BRAF or MEK inhibitors, similarly to other MDAs. Taken together, our study demonstrates the feasibility of using tandem MS as a means of discovering shared immunogenic tumor-associated epitopes and identifies SLC45A2 as a promising immunotherapeutic target for melanoma with high tumor selectivity and reduced potential for autoimmune toxicity.
UR - http://www.scopus.com/inward/record.url?scp=85026747911&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-17-0051
DO - 10.1158/2326-6066.CIR-17-0051
M3 - Article
C2 - 28630054
AN - SCOPUS:85026747911
SN - 2326-6066
VL - 5
SP - 618
EP - 629
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 8
ER -