Integrating genome-wide CRISPR immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulators
Background Despite approval of immunotherapy for a wide range of cancers, the majority of patients fail to respond to immunotherapy or relapse following initial response. These failures may be attributed to immunosuppressive mechanisms co-opted by tumor cells. However, it is challenging to use conve...
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doaj-697d4fd89d6e46368db75489c262a0192021-09-22T14:30:04ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-02-019210.1136/jitc-2020-001819Integrating genome-wide CRISPR immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulatorsYuan Chen0Jiakai Hou1Leilei Shi2Ke Pan3Ritu Bohat4Nicholas A. Egan5Jodi A. McKenzie6Rina M. Mbofung7Leila J. Williams8Zhenhuang Yang9Xiaofang Liang10Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Biology and Biochemistry, University of Houston, Houston, Texas, USADepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Biology and Biochemistry, University of Houston, Houston, Texas, USADepartment of Biology and Biochemistry, University of Houston, Houston, Texas, USADepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Biology and Biochemistry, University of Houston, Houston, Texas, USABackground Despite approval of immunotherapy for a wide range of cancers, the majority of patients fail to respond to immunotherapy or relapse following initial response. These failures may be attributed to immunosuppressive mechanisms co-opted by tumor cells. However, it is challenging to use conventional methods to systematically evaluate the potential of tumor intrinsic factors to act as immune regulators in patients with cancer.Methods To identify immunosuppressive mechanisms in non-responders to cancer immunotherapy in an unbiased manner, we performed genome-wide CRISPR immune screens and integrated our results with multi-omics clinical data to evaluate the role of tumor intrinsic factors in regulating two rate-limiting steps of cancer immunotherapy, namely, T cell tumor infiltration and T cell-mediated tumor killing.Results Our studies revealed two distinct types of immune resistance regulators and demonstrated their potential as therapeutic targets to improve the efficacy of immunotherapy. Among them, PRMT1 and RIPK1 were identified as a dual immune resistance regulator and a cytotoxicity resistance regulator, respectively. Although the magnitude varied between different types of immunotherapy, genetically targeting PRMT1 and RIPK1 sensitized tumors to T-cell killing and anti-PD-1/OX40 treatment. Interestingly, a RIPK1-specific inhibitor enhanced the antitumor activity of T cell-based and anti-OX40 therapy, despite limited impact on T cell tumor infiltration.Conclusions Collectively, the data provide a rich resource of novel targets for rational immuno-oncology combinations.https://jitc.bmj.com/content/9/2/e001819.full |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yuan Chen Jiakai Hou Leilei Shi Ke Pan Ritu Bohat Nicholas A. Egan Jodi A. McKenzie Rina M. Mbofung Leila J. Williams Zhenhuang Yang Xiaofang Liang |
spellingShingle |
Yuan Chen Jiakai Hou Leilei Shi Ke Pan Ritu Bohat Nicholas A. Egan Jodi A. McKenzie Rina M. Mbofung Leila J. Williams Zhenhuang Yang Xiaofang Liang Integrating genome-wide CRISPR immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulators Journal for ImmunoTherapy of Cancer |
author_facet |
Yuan Chen Jiakai Hou Leilei Shi Ke Pan Ritu Bohat Nicholas A. Egan Jodi A. McKenzie Rina M. Mbofung Leila J. Williams Zhenhuang Yang Xiaofang Liang |
author_sort |
Yuan Chen |
title |
Integrating genome-wide CRISPR immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulators |
title_short |
Integrating genome-wide CRISPR immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulators |
title_full |
Integrating genome-wide CRISPR immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulators |
title_fullStr |
Integrating genome-wide CRISPR immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulators |
title_full_unstemmed |
Integrating genome-wide CRISPR immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulators |
title_sort |
integrating genome-wide crispr immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulators |
publisher |
BMJ Publishing Group |
series |
Journal for ImmunoTherapy of Cancer |
issn |
2051-1426 |
publishDate |
2021-02-01 |
description |
Background Despite approval of immunotherapy for a wide range of cancers, the majority of patients fail to respond to immunotherapy or relapse following initial response. These failures may be attributed to immunosuppressive mechanisms co-opted by tumor cells. However, it is challenging to use conventional methods to systematically evaluate the potential of tumor intrinsic factors to act as immune regulators in patients with cancer.Methods To identify immunosuppressive mechanisms in non-responders to cancer immunotherapy in an unbiased manner, we performed genome-wide CRISPR immune screens and integrated our results with multi-omics clinical data to evaluate the role of tumor intrinsic factors in regulating two rate-limiting steps of cancer immunotherapy, namely, T cell tumor infiltration and T cell-mediated tumor killing.Results Our studies revealed two distinct types of immune resistance regulators and demonstrated their potential as therapeutic targets to improve the efficacy of immunotherapy. Among them, PRMT1 and RIPK1 were identified as a dual immune resistance regulator and a cytotoxicity resistance regulator, respectively. Although the magnitude varied between different types of immunotherapy, genetically targeting PRMT1 and RIPK1 sensitized tumors to T-cell killing and anti-PD-1/OX40 treatment. Interestingly, a RIPK1-specific inhibitor enhanced the antitumor activity of T cell-based and anti-OX40 therapy, despite limited impact on T cell tumor infiltration.Conclusions Collectively, the data provide a rich resource of novel targets for rational immuno-oncology combinations. |
url |
https://jitc.bmj.com/content/9/2/e001819.full |
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