Abstract
The immune function within the tumor microenvironment has become a prominent therapeutic target, with tumor-associated macrophages (TAMs) playing a critical role in immune suppression. We propose an 89Zr-labeled high-density lipoprotein (89Zr-HDL) nanotracer as a means of monitoring response to immunotherapy. Methods: Female MMTV-PyMT mice were treated with pexidartinib, a colony-stimulating factor 1 receptor (CSF1R) inhibitor, to reduce TAM density. The accumulation of 89Zr-HDL within the tumor was assessed using PET/CT imaging and autoradiography, whereas TAM burden was determined using immunofluorescence. Results: A significant reduction in 89Zr-HDL accumulation was observed in PET/CT images, with 2.9% ± 0.3% and 3.7% ± 0.2% injected dose/g for the pexidartinib- and vehicle-treated mice, respectively. This reduction was corroborated ex vivo and correlated with decreased TAM density. Conclusion: These results support the potential use of 89Zr-HDL nanoparticles as a PET tracer to quickly monitor the response to CSF1R inhibitors and other therapeutic strategies targeting TAMs.
Highlights
Breast cancer is the second leading cause of cancer-related death for women in the United States
Tumor-associated macrophage (TAM) burden has been correlated with rapid tumor growth, metastatic potential, and poor patient prognosis [12]
We explore the use of 89Zr-labeled reconstituted high-density lipoprotein (HDL) as a macrophage-targeted diagnostic tool that might help clinicians more quickly and accurately assess the response to anti-tumor-associated macrophages (TAMs) immunotherapies
Summary
Breast cancer is the second leading cause of cancer-related death for women in the United States. Most patients do not present with metastatic lesions in distant tissue on initial diagnosis, 1 in 3 women with node-negative and an even larger percentage of those with node-positive breast cancer will eventually develop distant metastases [2]. The accumulation of macrophages within the tumor and their shift toward an alternatively activated phenotype results in signaling cascades that induce angiogenesis, alter the extracellular matrix, and suppress adaptive immune response [9,10,11]. There are numerous clinical trials exploring the use of CSF1R inhibitors as a monotherapy or in combination with other therapeutic strategies in various types of cancer [14]. Pexidartinib (PLX3397), a CSF1R inhibitor currently in phase 3 clinical trials, has shown promising results as a monotherapy and in combination with immune checkpoint therapies [14]. The biodistribution of 89Zr-HDL nanoparticles, the accumulation in the tumor, was analyzed and compared in pexidartinib-treated and untreated MMTV-PyMT mice (Supplemental Fig. 1; supplemental materials are available at http://jnm.snmjournals.org)
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