Enhanced Survival with Implantable Scaffolds That Capture Metastatic Breast Cancer Cells In Vivo

Abstract

The onset of distant organ metastasis from primary breast cancer marks the transition to a stage IV diagnosis. Standard imaging modalities often detect distant metastasis when the burden of disease is high, underscoring the need for improved methods of detection to allow for interventions that would impede disease progression. Here, micro-porous poly(ε-caprolactone) scaffolds were developed that capture early metastatic cells and thus serve as a sentinel for early detection. These scaffolds were used to characterize the dynamic immune response to the implant spanning the acute and chronic foreign body response. The immune cell composition had stabilized at the scaffold after approximately 1 month, and changed dramatically within days to weeks after tumor inoculation, with CD11b + Gr1 hi Ly6C − cells having the greatest increase in abundance. Implanted scaffolds recruited metastatic cancer cells that were inoculated into the mammary fat pad in vivo, Disclosure of Potential Conflicts of Interest:The authors have nothing to disclose. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript which also significantly reduced tumor burden in the liver and brain. Additionally, cancer cells could be detected using a label-free imaging modality termed inverse spectroscopic optical coherence tomography, and we tested the hypothesis that subsequent removal of the primary tumor after early detection would enhance survival. Surgical removal of the primary tumor following cancer cell detection in the scaffold significantly improved disease-specific survival. The enhanced disease-specific survival was associated with a systemic reduction in the CD11b + Gr1 hi Ly6C − cells as a consequence of the implant, which was further supported by Gr-1 depletion studies. Implementation of the scaffold may provide diagnostic and therapeutic options for cancer patients in both the high-risk and adjuvant treatment settings.

Microporous scaffolds loaded with immunomodulatory lentivirus to study the contribution of immune cell populations to tumor cell recruitment in vivo

“…Second, strategies to probe the premetastatic niche have often employed genetic modifications that impact the entire organism, typically with off‐target effects on primary tumor development (Peinado et al, ). Biomaterial scaffolds have recently emerged as tools to investigate tumor cell abundance in predefined sites and to alter the local microenvironment without altering the primary tumor cells or host organism (Aguado, Bushnell, Rao, Jeruss, & Shea, ; Aguado et al, ; Aguado et al, ; Aguado et al, ; Azarin et al, ; Bersani et al, ; Bushnell et al, ; Ko et al, ; J. Lee et al, ; Rao et al, ).…”

“…In this report, we hypothesized that local modulation of the immune microenvironment could serve as a means to influence tumor cell abundance and to dissect the contribution of specific immune cell populations to the recruitment of tumor cells to a metastatic site. Biomaterials that recruit metastatic cancer cells in vivo are an emerging technology to investigate tumor cell abundance and phenotype at a premetastatic niche (Aguado et al, ; Aguado et al, ; Aguado et al, ; Aguado et al, ; Azarin et al, ; Bersani et al, ; Ko et al, ; J. Lee et al, ; Rao et al, ). First, they provide a defined site in vivo to which tumor cells are recruited.…”

Progress on Modulating Tumor‐Associated Macrophages with Biomaterials

“…Another biomaterial‐based strategy utilized scaffolds to influence immune cell distribution, reducing TAM populations in the primary tumors and attenuating their tumor supporting activities. Rao et al implanted microporous poly(ε‐caprolactone) (PCL) scaffolds, which recruited immune cells and reduced tumor burden at metastatic sites . At the site of the scaffolds, increases in inflammatory (Ly6C + F4/80 − ) and noninflammatory monocytes (CD11b + Gr‐1 hi Ly6C − ) were detected; both cell populations have been implicated in preparing premetastatic niches.…”

Engineering Biomaterials to Direct Innate Immunity

“…[66][67][68] In mice receiving either a polymer scaffold or mock surgery, TAMs from primary tumors were separated based on their expression of Vcam1, which is indicative of bloodborne macrophages, as opposed to tissue-resident macrophages. Microporous polymer implants designed to facilitate tissue ingrowth and capture of metastatic tumor cells for early detection have recently been studied for their impact on the gene expression of innate immune cells in the primary tumor.…”