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

Abstract

Monitoring metastatic events in distal tissues is challenged by their sporadic occurrence in obscure and inaccessible locations within these vital organs. A synthetic biomaterial scaffold can function as a synthetic metastatic niche to reveal the nature of these distal sites. These implanted scaffolds promote tissue ingrowth, which upon cancer initiation is transformed into a metastatic niche that captures aggressive circulating tumor cells. We hypothesized that immune cell phenotypes at synthetic niches reflect the immunosuppressive conditioning within a host that contributes to metastatic cell recruitment and can identify disease progression and response to therapy. We analyzed the expression of 632 immune-centric genes in tissue biopsied from implants at weekly intervals following inoculation. Specific immune populations within implants were then analyzed by single-cell RNA-seq. Dynamic gene expression profiles in innate cells, such as myeloid-derived suppressor cells, macrophages, and dendritic cells, suggest the development of an immunosuppressive microenvironment. These dynamics in immune phenotypes at implants was analogous to that in the diseased lung and had distinct dynamics compared with blood leukocytes. Following a therapeutic excision of the primary tumor, longitudinal tracking of immune phenotypes at the implant in individual mice showed an initial response to therapy, which over time differentiated recurrence versus survival. Collectively, the microenvironment at the synthetic niche acts as a sentinel by reflecting both progression and regression of disease. Significance: Immune dynamics at biomaterial implants, functioning as a synthetic metastatic niche, provides unique information that correlates with disease progression.

Engineered immunological niches to monitor disease activity and treatment efficacy in relapsing multiple sclerosis

“…We developed an implantable IN that forms a vascularized inflammatory tissue that is dynamic with the status of the immune system. This finding is well supported by reports demonstrating that inflammation surrounding implants is altered by systemic changes associated with various physiological and pathological states, including diabetes, obesity, cancer, and advanced age [22][23][24][25][26] . This implantable biopsy site thus harnesses the host immune system to identify immunological changes within innate immune cells of tissues, which contribute to disease initiation and progression.…”

Pancreatic cancer is marked by complement-high blood monocytes and tumor-associated macrophages

“…Biomaterial scaffolds model the pre-metastatic niche ( Azarin et al, 2015 ; Rao et al, 2016 ; Bushnell et al, 2019 ) and allow for repeated sampling, and, thus, longitudinal analyses. Furthermore, scaffolds model natural secondary sites of metastasis and are distinct from blood, as recently determined ( Oakes et al, 2020 ; Morris et al, 2020a ). Relevant to our study, myeloid cells entering scaffolds differentiate into macrophages, distinct from peripheral blood monocytes.…”

The Role of Non-Canonical Hsp70s (Hsp110/Grp170) in Cancer

“…Cancer cells are subjected to several forms of physiological insults, including anticancer interventions-induced stress, immune response, elevated reactive oxygen species, enhanced hypoxic and acidic conditions [ 62 , 63 ]. Under these conditions, the stress buffering role of Hsp110 becomes apparent.…”