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Proc Natl Acad Sci U S A. 2019 Aug 20;116(34):16971-16980. doi: 10.1073/pnas.1905005116. Epub 2019 Aug 2.

Immuno-PET identifies the myeloid compartment as a key contributor to the outcome of the antitumor response under PD-1 blockade.

Author information

1
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.
2
Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
3
Department of Imaging, Dana-Farber Cancer Institute, Boston, MA 02215.
4
Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115.
5
Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
6
Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
7
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.
8
Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215.
9
Department of Biology, Massachusetts Institute of Technology, Cambridge MA 02139.
10
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
11
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115; hidde.ploegh@childrens.harvard.edu.

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.

KEYWORDS:

PET imaging; checkpoint blockade; nanobodies; single-cell RNA sequencing; tumor immune microenvironment

PMID:
31375632
PMCID:
PMC6708368
[Available on 2020-02-02]
DOI:
10.1073/pnas.1905005116

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