Absolute quantification of tumor antigens using embedded MHC-I isotopologue calibrants

Absolute quantification measurements (copies per cell) of peptide major histocompatibility complex (pMHC) antigens are necessary to inform targeted immunotherapy drug design; however, existing methods for absolute quantification have critical limitations. Here, we present a platform termed SureQuant...

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Bibliographic Details
Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 37; pp. 1 - 3
Main Authors:	Stopfer, Lauren E., Gajadhar, Aaron S., Patel, Bhavin, Gallien, Sebastien, Frederick, Dennie T., Boland, Genevieve M., Sullivan, Ryan J., White, Forest M.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 14-09-2021
Series:	Brief Report
Subjects:	Antigen (tumor-associated) Antigen Presentation - drug effects Antigen Presentation - immunology Antigens Antigens, Neoplasm - analysis Antigens, Neoplasm - drug effects Antigens, Neoplasm - immunology Benzimidazoles - pharmacology Biological Sciences BRIEF REPORTS Calibration Drug development Histocompatibility Antigens Class I - immunology Histocompatibility Antigens Class I - metabolism Humans Immunotherapy Major histocompatibility complex MAP Kinase Kinase 1 - antagonists & inhibitors Mass spectrometry Mass spectroscopy MEK inhibitors Melanoma Melanoma - drug therapy Melanoma - immunology Melanoma - metabolism Tumor Cells, Cultured Tumors antigen presentation MHC class I immunopeptidomics
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Summary:	Absolute quantification measurements (copies per cell) of peptide major histocompatibility complex (pMHC) antigens are necessary to inform targeted immunotherapy drug design; however, existing methods for absolute quantification have critical limitations. Here, we present a platform termed SureQuant-IsoMHC, utilizing a series of pMHC isotopologues and internal standard-triggered targeted mass spectrometry to generate an embedded multipoint calibration curve to determine endogenous pMHC concentrations for a panel of 18 tumor antigens. We apply SureQuant-IsoMHC to measure changes in expression of our target panel in a melanoma cell line treated with a MEK inhibitor and translate this approach to estimate antigen concentrations in melanoma tumor biopsies.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: L.E.S., A.S.G., B.P., S.G., D.T.F., G.M.B., R.J.S., and F.M.W. designed research; L.E.S. and D.T.F. performed research; B.P. and S.G. contributed new reagents/analytic tools; L.E.S. analyzed data; and L.E.S., A.S.G., B.P., S.G., D.T.F., G.M.B., R.J.S., and F.M.W. wrote the paper. Edited by K. Christopher Garcia, Stanford University, Stanford, CA, and approved August 2, 2021 (received for review June 22, 2021)
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.2111173118