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

Mohammad Rashidian ¹, Martin W LaFleur ², Vincent L Verschoor ¹, Anushka Dongre ³, Yun Zhang ³, Thao H Nguyen ², Stephen Kolifrath ¹, Amir R Aref ⁴, Christie J Lau ⁴, Cloud P Paweletz ⁴, Xia Bu ⁴, Gordon J Freeman ⁴, M Inmaculada Barrasa ³, Robert A Weinberg ³, Arlene H Sharpe ², Hidde L Ploegh ⁵

Affiliations

¹ Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.
² Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115.
³ Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.
⁵ Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115; hidde.ploegh@childrens.harvard.edu.

PMID: 31375632
45 References
45 citations

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.

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