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Immuno-PET identifies the myeloid compartment as a key contributor to the outcome of the antitumor response under PD-1 blockade
- Source :
- Proceedings of the National Academy of Sciences of the United States of America. 116(34)
- Publication Year :
- 2019
-
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 (89)Zr-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.
- Subjects :
- Myeloid
medicine.medical_treatment
Population
Programmed Cell Death 1 Receptor
Adenocarcinoma
CD8-Positive T-Lymphocytes
Mice
Antigens, Neoplasm
Cell Line, Tumor
medicine
Tumor Microenvironment
Distribution (pharmacology)
Animals
education
education.field_of_study
Multidisciplinary
CD11b Antigen
biology
Chemistry
RNA
Immunotherapy
Neoplasms, Experimental
Neoplasm Proteins
medicine.anatomical_structure
Integrin alpha M
PNAS Plus
Positron-Emission Tomography
Cancer research
biology.protein
Female
Antibody
Colorectal Neoplasms
CD8
Subjects
Details
- ISSN :
- 10916490
- Volume :
- 116
- Issue :
- 34
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....42a6686c6e226e4e2be2e51fc20d5d73