In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 34 ( 2019-08-20), p. 16971-16980
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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1905005116
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2019
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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