dc.contributor.author | Weinberg, Robert A. (Robert Allan), 1942- | |
dc.date.accessioned | 2020-03-30T13:47:53Z | |
dc.date.available | 2020-03-30T13:47:53Z | |
dc.date.issued | 2019-08-02 | |
dc.identifier.issn | 0027-8424 | |
dc.identifier.issn | 1091-6490 | |
dc.identifier.uri | https://hdl.handle.net/1721.1/124404 | |
dc.description.abstract | Immunotherapy 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.sponsorship | Lustgarten Foundation (P01 CA080111) | en_US |
dc.language.iso | en | |
dc.publisher | Proceedings of the National Academy of Sciences | en_US |
dc.relation.isversionof | 10.1073/pnas.1905005116 | en_US |
dc.rights | Article 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.source | PNAS | en_US |
dc.subject | Multidisciplinary | en_US |
dc.title | Immuno-PET identifies the myeloid compartment as a key contributor to the outcome of the antitumor response under PD-1 blockade | en_US |
dc.type | Article | en_US |
dc.identifier.citation | Rashidian, 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.department | Massachusetts Institute of Technology. Department of Biology | en_US |
dc.relation.journal | Proceedings of the National Academy of Sciences of the United States of America | en_US |
dc.eprint.version | Final published version | en_US |
dc.type.uri | http://purl.org/eprint/type/JournalArticle | en_US |
eprint.status | http://purl.org/eprint/status/PeerReviewed | en_US |
dc.date.updated | 2020-02-12T18:58:26Z | |
dspace.date.submission | 2020-02-12T18:58:27Z | |
mit.journal.volume | 116 | en_US |
mit.journal.issue | 34 | en_US |
mit.license | PUBLISHER_POLICY | |
mit.metadata.status | Complete | |