Defining HLA-II Ligand Processing and Binding Rules with Mass Spectrometry Enhances Cancer Epitope Prediction

被引：170

作者：

Abelin, Jennifer G. ^{[1
]}

Harjanto, Dewi ^{[1
]}

Malloy, Matthew ^{[1
]}

Suri, Prerna ^{[1
]}

Colson, Tyler ^{[1
]}

Goulding, Scott P. ^{[1
]}

Creech, Amanda L. ^{[1
]}

Serrano, Lia R. ^{[1
]}

Nasir, Gibran ^{[1
]}

Nasrullah, Yusuf ^{[1
]}

McGann, Christopher D. ^{[1
]}

Velez, Diana ^{[1
]}

Ting, Ying S. ^{[1
]}

Poran, Asaf ^{[1
]}

Rothenberg, Daniel A. ^{[1
]}

Chhangawala, Sagar ^{[1
]}

Rubinsteyn, Alex ^{[2
]}

Hammerbacher, Jeff ^{[2
]}

Gaynor, Richard B. ^{[1
]}

Fritsch, Edward F. ^{[1
]}

Greshock, Joel ^{[1
]}

Oslund, Rob C. ^{[1
]}

Barthelme, Dominik ^{[1
]}

Addona, Terri A. ^{[1
]}

Arleta, Christina M. ^{[1
]}

Rooney, Michael S. ^{[1
]}

机构：

[1] Neon Therapeut, Cambridge, MA 02139 USA

[2] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

来源：

IMMUNITY | 2019年 / 51卷 / 04期

关键词：

INVARIANT CHAIN; PEPTIDES; MELANOMA; MOLECULES; COMPLEX; CELLS; UBIQUITINATION; QUANTIFICATION; IMMUNOTHERAPY; DEGRADATION;

D O I：

10.1016/j.immuni.2019.08.012

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Increasing evidence indicates CD4(+) T cells can recognize cancer-specific antigens and control tumor growth. However, it remains difficult to predict the antigens that will be presented by human leukocyte antigen class II molecules (HLA-II), hindering efforts to optimally target them therapeutically. Obstacles include inaccurate peptide-binding prediction and unsolved complexities of the HLA-II pathway. To address these challenges, we developed an improved technology for discovering HLA-II binding motifs and conducted a comprehensive analysis of tumor ligandomes to learn processing rules relevant in the tumor microenvironment. We profiled >40 HLA-II alleles and showed that binding motifs were highly sensitive to HLA-DM, a peptide-loading chaperone. We also revealed that intratumoral HLA-II presentation was dominated by professional antigen-presenting cells (APCs) rather than cancer cells. Integrating these observations, we developed algorithms that accurately predicted APC ligandomes, including peptides from phagocytosed cancer cells. These tools and biological insights will enable improved HLA-II-directed cancer therapies.

引用

页码：766 / +

页数：31

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