TY - JOUR
T1 - Immunogenomic Landscape Contributes to Hyperprogressive Disease after Anti-PD-1 Immunotherapy for Cancer
AU - Xiong, Donghai
AU - Wang, Yian
AU - Singavi, Arun K.
AU - Mackinnon, Alexander C.
AU - George, Ben
AU - You, Ming
N1 - Funding Information:
We thank the outside reviewers for manuscript suggestions and revisions. This work was supported by NIH grants N01CN201200015 and R01CA134682. M.Y. and Y.W. conceived the project and revised the manuscript. D.X. performed the experiment and all the data analyses and writing of the paper. A.K.S and A.C.M collected the samples for this study. B.G. recruited the patients and revised the manuscript. The authors declare no competing interests.
Funding Information:
We thank the outside reviewers for manuscript suggestions and revisions. This work was supported by NIH grants N01CN201200015 and R01CA134682 .
Publisher Copyright:
© 2018 The Authors
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2018/11/30
Y1 - 2018/11/30
N2 - Although PD-1-blocking immunotherapies demonstrate significant therapeutic promise, a subset of the patients could develop hyperprogressive disease (HPD) with accelerated tumor growth after anti-PD1 immunotherapy. To elucidate the underlying mechanisms, we compared the mutational and transcriptional landscapes between the pre- and post-therapy tumors of two patients developing HPD after anti-PD-1 immunotherapy. In post-therapy HPD tumors, somatic mutations were found in known cancer genes, including tumor suppressor genes such as TSC2 and VHL, along with transcriptional upregulation of oncogenic pathways, including IGF-1, ERK/MAPK, PI3K/AKT, and TGF-β. We found that post-therapy HPD tumors were less immunogenic than pre-therapy tumors, concurrent with an increased presence of ILC3 cells, a subset of innate lymphoid cells. We also developed a gene expression signature predictive of HPD. In summary, we identified the genomics and immune features associated with HPD, which may help identify patients at risk of adverse clinical outcome after anti-PD-1 immunotherapy. Physiology (170590663/189723279); Immunology (186131996Physiology; Biotechnology; Cell Biology; Omics
AB - Although PD-1-blocking immunotherapies demonstrate significant therapeutic promise, a subset of the patients could develop hyperprogressive disease (HPD) with accelerated tumor growth after anti-PD1 immunotherapy. To elucidate the underlying mechanisms, we compared the mutational and transcriptional landscapes between the pre- and post-therapy tumors of two patients developing HPD after anti-PD-1 immunotherapy. In post-therapy HPD tumors, somatic mutations were found in known cancer genes, including tumor suppressor genes such as TSC2 and VHL, along with transcriptional upregulation of oncogenic pathways, including IGF-1, ERK/MAPK, PI3K/AKT, and TGF-β. We found that post-therapy HPD tumors were less immunogenic than pre-therapy tumors, concurrent with an increased presence of ILC3 cells, a subset of innate lymphoid cells. We also developed a gene expression signature predictive of HPD. In summary, we identified the genomics and immune features associated with HPD, which may help identify patients at risk of adverse clinical outcome after anti-PD-1 immunotherapy. Physiology (170590663/189723279); Immunology (186131996Physiology; Biotechnology; Cell Biology; Omics
KW - )
KW - Biotechnology
KW - Cell Biology
KW - Immunology (186131996Physiology
KW - Omics
KW - Physiology (170590663/189723279
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U2 - 10.1016/j.isci.2018.10.021
DO - 10.1016/j.isci.2018.10.021
M3 - Article
AN - SCOPUS:85064993721
VL - 9
SP - 258
EP - 277
JO - iScience
JF - iScience
SN - 2589-0042
ER -