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dc.contributor.authorWeinberg, Robert A. (Robert Allan), 1942-
dc.date.accessioned2020-03-30T13:47:53Z
dc.date.available2020-03-30T13:47:53Z
dc.date.issued2019-08-02
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.urihttps://hdl.handle.net/1721.1/124404
dc.description.abstractImmunotherapy using checkpoint-blocking antibodies against PD-1 has produced impressive results in a wide range of cancers. However, the response remains heterogeneous among patients. We used noninvasive immuno-positron emission tomography (PET), using 89Zr-labeled PEGylated single-domain antibody fragments (nanobodies or VHHs), to explore the dynamics and distribution of intratumoral CD8+ T cells and CD11b+ myeloid cells in response to anti–PD-1 treatment in the MC38 colorectal mouse adenocarcinoma model. Responding and nonresponding tumors showed consistent differences in the distribution of CD8+ and CD11b+ cells. Anti–PD-1 treatment mobilized CD8+ T cells from the tumor periphery to a more central location. Only those tumors fully infiltrated by CD8+ T cells went on to complete resolution. All tumors contained CD11b+ myeloid cells from the outset of treatment, with later recruitment of additional CD11b+ cells. As tumors grew, the distribution of intratumoral CD11b+ cells became more heterogeneous. Shrinkage of tumors in responders correlated with an increase in the CD11b+ population in the center of the tumors. The changes in distribution of CD8+ and CD11b+ cells, as assessed by PET, served as biomarkers to gauge the efficacy of anti–PD-1 treatment. Single-cell RNA sequencing of RNA from intratumoral CD45+ cells showed that CD11b+ cells in responders and nonresponders were markedly different. The responders exhibited a dominant population of macrophages with an M1-like signature, while the CD45+ population in the nonresponders displayed an M2-like transcriptional signature. Thus, by using immuno-PET and single-cell RNA sequencing, we show that anti–PD-1 treatment not only affects interactions of CD8+ T cells with the tumor but also impacts the intratumoral myeloid compartment.en_US
dc.description.sponsorshipLustgarten Foundation (P01 CA080111)en_US
dc.language.isoen
dc.publisherProceedings of the National Academy of Sciencesen_US
dc.relation.isversionof10.1073/pnas.1905005116en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourcePNASen_US
dc.subjectMultidisciplinaryen_US
dc.titleImmuno-PET identifies the myeloid compartment as a key contributor to the outcome of the antitumor response under PD-1 blockadeen_US
dc.typeArticleen_US
dc.identifier.citationRashidian, Mohammad et al. "Immuno-PET identifies the myeloid compartment as a key contributor to the outcome of the antitumor response under PD-1 blockade." Proceedings of the National Academy of Sciences of the United States of America 116 (2019):16971-16980 © 2019 The Author(s)en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.relation.journalProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2020-02-12T18:58:26Z
dspace.date.submission2020-02-12T18:58:27Z
mit.journal.volume116en_US
mit.journal.issue34en_US
mit.licensePUBLISHER_POLICY
mit.metadata.statusComplete


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