@article{29a30ab890d34b5fa4c4933d9cc661fd,
title = "Removal of N-Linked Glycosylation Enhances PD-L1 Detection and Predicts Anti-PD-1/PD-L1 Therapeutic Efficacy",
abstract = "Reactivation of T cell immunity by PD-1/PD-L1 immune checkpoint blockade has been shown to be a promising cancer therapeutic strategy. However, PD-L1 immunohistochemical readout is inconsistent with patient response, which presents a clinical challenge to stratify patients. Because PD-L1 is heavily glycosylated, we developed a method to resolve this by removing the glycan moieties from cell surface antigens via enzymatic digestion, a process termed sample deglycosylation. Notably, deglycosylation significantly improves anti-PD-L1 antibody binding affinity and signal intensity, resulting in more accurate PD-L1 quantification and prediction of clinical outcome. This proposed method of PD-L1 antigen retrieval may provide a practical and timely approach to reduce false-negative patient stratification for guiding anti-PD-1/PD-L1 therapy. Histological detection of PD-L1 may guide therapy with anti-PD-1/PD-L1 antibodies but some PD-L1-negative tumors respond to these treatments. Lee et al. show that enzymatic deglycosylation of tissue sections improves PD-L1 detection and its predictive value, and could potentially impact patient stratification.",
keywords = "PD-1, PD-L1, antibody-based detection, biomarker, glycosylation/deglycosylation, heterogeneity/homogeneity, immune checkpoint, immunohistochemistry, immunotherapy",
author = "Lee, {Heng Huan} and Wang, {Ying Nai} and W. Xia and Chen, {Chia Hung} and Rau, {Kun Ming} and Leiguang Ye and Yongkun Wei and Chou, {Chao Kai} and Wang, {Shao Chun} and M. Yan and Tu, {Chih Yen} and Hsia, {Te Chun} and Chiang, {Shu Fen} and Chao, {K. S.Clifford} and Wistuba, {Ignacio I.} and Hsu, {Jennifer L.} and Hortobagyi, {Gabriel N.} and Hung, {Mien Chie}",
note = "Funding Information: We thank John V. Heymach, Lauren A. Bayers, and Carl M. Gay at MD Anderson Cancer Center for their constructive advice on clinical input. This work was partially supported by the following: Ruth Leggett Distinguished Chair Endowment ; MDA Startup Fund ; The University of Texas MD Anderson - China Medical University, Taiwan and Hospital Sister Institution Fund ; Breast Cancer Research Foundation ( BCRF-17-069 ); Cancer Prevention and Research Institute of Texas (Multi-Investigator Research Awards; RP160710 ); T32 Training Grant in Cancer Biology ( 5T32CA186892 to H.-H.L.); The Ministry of Health and Welfare , China Medical University Hospital Cancer Research Center of Excellence ( MOHW108-TDU-B-212-124024 ; MOHW108-TDU-B-212-122015 to S.-C.W.); The Drug Development Center, China Medical University from the Featured Areas Research Center Program within the Framework of the Higher Education Sprout Program by Ministry of Education (to S.-C.W.); Cancer Center Support Grant ( NIH P30 CA016672 ); and Center for Biological Pathways . Funding Information: We thank John V. Heymach, Lauren A. Bayers, and Carl M. Gay at MD Anderson Cancer Center for their constructive advice on clinical input. This work was partially supported by the following: Ruth Leggett Distinguished Chair Endowment; MDA Startup Fund; The University of Texas MD Anderson-China Medical University, Taiwan and Hospital Sister Institution Fund; Breast Cancer Research Foundation (BCRF-17-069); Cancer Prevention and Research Institute of Texas (Multi-Investigator Research Awards; RP160710); T32 Training Grant in Cancer Biology (5T32CA186892 to H.-H.L.); The Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence (MOHW108-TDU-B-212-124024; MOHW108-TDU-B-212-122015 to S.-C.W.); The Drug Development Center, China Medical University from the Featured Areas Research Center Program within the Framework of the Higher Education Sprout Program by Ministry of Education (to S.-C.W.); Cancer Center Support Grant (NIH P30 CA016672); and Center for Biological Pathways. H.-H.L. Y.-N.W. and M.-C.H. designed the study and drafted the manuscript. W.X. and Y.W. performed the IHC experiments and provided pathological assistance. H.-H.L. Y.-N.W. and C.-K.C. performed the laboratory experiments and analyzed the data. J.L.H. contributed to the preparation of the manuscript. C.-H.C. K.-M.R. L.Y. S.-C.W. M.Y. C.-Y.T. and T.-C.H. provided patient sample slides with clinical information and analyzed the data. S.-F.C. and K.S.C.C. provided rectal cancer tissue microarray with clinical information. I.I.W. contributed to pathological input and data analysis. G.N.H. provided scientific and clinical input. M.-C.H. supervised the project and managed the funding acquisition. All authors reviewed the manuscript, provided feedback, and approved the manuscript in its final form. H.-H.L. Y.-N.W. and M.-C.H. are listed as inventors on a patent application (No. PCT/US2019/036073, entitled Detection of immune checkpoint molecules by deglycosylation) submitted by The University of Texas MD Anderson Cancer Center. All other authors declare no non-financial and financial competing interests. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = aug,
day = "12",
doi = "10.1016/j.ccell.2019.06.008",
language = "English (US)",
volume = "36",
pages = "168--178.e4",
journal = "Cancer cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "2",
}