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

Abstract

Metastases are preceded by stochastic formation of a hospitable microenvironment known as the premetastatic niche, which has been difficult to study. Herein, we employ implantable polycaprolactone scaffolds as an engineered premetastatic niche to independently investigate the role of interleukin‐10 (IL10), CXCL12, and CCL2 in recruiting immune and tumor cells and impacting breast cancer cell phenotype via lentiviral overexpression. Lentivirus delivered from scaffolds in vivo achieved sustained transgene expression for 56 days. IL10 lentiviral expression, but not CXCL12 or CCL2, significantly decreased tumor cell recruitment to scaffolds in vivo. Delivery of CXCL12 enhanced CD45+ immune cell recruitment to scaffolds while delivery of IL10 reduced immune cell recruitment. CCL2 did not alter immune cell recruitment. Tumor cell phenotype was investigated using conditioned media from immunomodulated scaffolds, with CXCL12 microenvironments reducing proliferation, and IL10 microenvironments enhancing proliferation. Migration was enhanced with CCL2 and reduced with IL10‐driven microenvironments. Multiple linear regression identified populations of immune cells associated with tumor cell abundance. CD45+ immune and CD8+ T cells were associated with reduced tumor cell abundance, while CD11b+Gr1+ neutrophils and CD4+ T cells were associated with enhanced tumor cell abundance. Collectively, biomaterial scaffolds provide a tool to probe the formation and function of the premetastatic niche.

Metastatic Conditioning of Myeloid Cells at a Subcutaneous Synthetic Niche Reflects Disease Progression and Predicts Therapeutic Outcomes

“…3E). These results suggest that the foreign body response to the material largely determines immune recruitment to the scaffold, as supported by previous studies (17,18), and that the preexisting condition of the implant does not selectively control immune cell trafficking at the implant. Thus, the similarities in trafficking and phenotypic shifts in the scRNA-seq data illustrate that the synthetic niche provides both a predefined site for disease-conditioned immune cells to aggregate, then further differentiate into metastasis-supportive populations.…”

“…We and others have previously reported that biomaterial implants function as a synthetic metastatic niche, with recruitment of early metastatic cells that represent aggressive populations observed within the lung (11)(12)(13)(14)(15)(16)(17)(18)(19). The development of the metastatic niche is driven by circulating acellular material from the primary tumor that alters the immune system of the host, including discrete sites in distal organs (20)(21)(22)(23).…”

Engineered Niches to Analyze Mechanisms of Metastasis and Guide Precision Medicine

“…In both cases, delivered factors altered the immune cell composition of the implant. CCL22 increased metastatic tumor cell recruitment, while IL10 reduced tumor cell recruitment (20,33). Importantly, these studies highlight the mechanistic insights associated with manipulating the synthetic niche.…”

Breast cancer dormancy: need for clinically relevant models to address current gaps in knowledge

“…The second of these models was developed by the Shea lab and utilized a microporous polymer scaffold and implantation into tumor-bearing mice to generate a niche in vivo to which metastatic tumor cells home 113 – 115 . This approach facilitates the development and study of the metastatic niche in vivo and can be expanded via explantation of the engineered niche and subsequent culture in vitro 116 , 117 . The third model developed by the Lee lab utilizes a combination of the approaches 118 .…”