Purpose: Efforts have been devoted to select eligible candidates for PD-1/PD-L1 immune checkpoint blocker (ICB) immunotherapy. Here, we have a serendipitous finding of positron emitting tomography (PET) imaging tracer 2-[18F]FDG as a potential immunomodulator. Therefore, we hypothesize that 2-[18F]FDG could induce PD-L1 expression change and create an immune-favorable microenvironment for tumor immunotherapy. Experimental Design: We designed a series of assays to verify PD-L1 upregulation, and tested immunotherapy regimens based on 2-[18F]FDG and anti-PD-L1 mAb, as monotherapy and in combination, in fully immunocompetent mice of MC38 and CT26 models. PD-L1 expression and tumor microenvironment (TME) changes were analyzed by western blot, transcriptomics study and flow-cytometric analysis. Results: PD-L1 was upregulated in a time- and dose-dependent manner after being induced by 2-[18F]FDG. The activation of NF-κB/IRF3 pathway and STAT1/3-IRF1 pathway play crucial parts in modulating PD-L1 expression after DNA damage and repair. Improved αPD-L1 mAb utilization rate and significant tumor growth delay were observed when the personalized therapeutic alliance of 2-[18F]FDG stimulation and ICB were employed. In addition, combination of 2-[18F]FDG with αPD-L1 mAb could reprogram a TME from "cold" to "hot", to make low immunoactivity tumors sensitive to ICB therapy. Conclusions: In summary, this promising paradigm has the potential to expand the traditional tumor theranostics. [18F]FDG-based ICB immunotherapy is highly significant in enhancing anti-tumor effect.
The
stimulator of interferon genes (STING) is a pivotal protein
in the production of STING-dependent type I interferon, which has
the potential to enhance tumor rejection. The visualization of STING
in the tumor microenvironment is valuable for STING-related treatments,
but few STING imaging probes have been reported to date. In this study,
we developed a novel 18F-labeled agent ([18F]F-CRI1)
with an acridone core structure for the positron emission tomography
(PET) imaging of STING in CT26 tumors. The probe was successfully
prepared with a nanomolar STING binding affinity of K
d = 40.62 nM. [18F]F-CRI1 accumulated quickly
in the tumor sites and its uptake reached a maximum of 3.02 ±
0.42% ID/g after 1 h i.v. injection. The specificity of [18F]F-CRI1 was confirmed both in in vitro cell uptake and in vivo PET
imaging by blocking studies. Our findings suggest that [18F]F-CRI1 may be a potential agent for visualizing STING in the tumor
microenvironment.
This study aims to develop a novel
68
Ga-labeled
tracer,
which can covalently bind to albumin in vivo based on the maleimide–thiol
strategy, and to evaluate its potential applications using positron
emission tomography (PET).
68
Ga-labeled maleimide-monoamide-DOTA
(denoted as [
68
Ga]Ga-DM) was prepared conveniently with
a high radiochemical yield (>90%) and radiochemical purity (>99%).
Its molar activity was calculated as 249.60 ± 68.50 GBq/μmol,
and the octanol–water partition coefficient (Log
P
) was −3.15 ± 0.08 with good stabilities. In vitro experiments
showed that [
68
Ga]Ga-DM can bind to albumin efficiently
and rapidly, with a binding fraction of over 70%. High uptake and
excellent retention in blood were observed with a long half-life (
t
1/2Z
) of 190.15 ± 24.14 min, which makes
it possible for blood pool PET imaging with high contrast. The transient
micro-bleeding in the rat model was detected successfully with PET
imaging. In addition, the uptakes of [
68
Ga]Ga-DM in the
inflammatory popliteal lymph nodes depend on the severity (5.90% ID/g
and 2.32% ID/g vs 1.01% ID/g for healthy lymph nodes at 0.5 h post-injection)
indicating its feasibility for lymphatic imaging. In conclusion, a
novel
68
Ga-labeled tracer was prepared with high efficiency
and yield in mild conditions. Based on the promising properties of
bonding covalently to albumin, great stability, high blood contrast
with a long half-life, and well environmental tolerance, [
68
Ga]Ga-DM could be developed as a potential tracer for PET imaging
of blood pool, bleeding, and vascular permeability alteration diseases
in the clinic.
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