Biology subjects

Soloff, A. C.

Publications and source records attributed to Soloff, A. C..

3 recordsLinked to original sources

bioRxiv2026

Microplastics inhibit macrophage bioenergetics impairing homeostatic function and immune responsiveness

Since the 1950s, micro- and nanoplastics (MNPs) have become omnipresent, representing a novel environmental hazard which continually deposits in our airways. Pulmonary macrophages (pMacs) orchestrate the balance between inflammation and tolerance required for homeostasis of the lung and are among the first immune cells to encounter inhaled MNPs. Yet, how pMacs react to plastic deposition in the lung and implications for disease remain unknown. Here, we exposed mice in vivo, human precision-cut lung slices (hPCLS) ex vivo, and monocyte-derived macrophages and cell lines to polystyrene MNPs in vitro. MNP deposition in the lung and extrapulmonary tissues was determined over a 1-week period and pMacs from MNP-laden lungs isolated for RNA-sequencing. We compared the effects of MNPs or diesel exhaust particulate exposures on hPCLS viability and metabolism, monocyte-derived macrophage transcription, and macrophage mitochondrial function, inflammation, and antigen presentation. MNPs readily translocated the lung and were observed in all organs examined within 1-day. pMacs from MNP-exposed mice expressed transcriptional pathways associated with endocrine system disorders, tissue remodeling, and malignant disease. Macrophage phagocytosis was impaired through decreased mitochondrial function which could be rescued pharmacologically. MNPs inhibited the ability of macrophages to effectively present OVA-antigen preventing TCR-specific activation, an effect that could be restored by blocking PD-1/PD-L1. These findings indicate that MNPs impair macrophages via unique mechanisms linking phagocytic and bioenergetic dysfunction. Loss of antigen-presenting capabilities in MNP-laden macrophages may compromise immunosurveillance. As such, MNPs have the potential to increase susceptibility to lung disease independent of the conventional mechanisms of inflammation and oxidative stress. Clinical relevanceO_LIBioaccumulation of micro- and nanoplastics in macrophages impairs their ability to function as antigen-presenting cells increasing susceptibility to pathogenic and malignant disease. C_LIO_LIPulmonary macrophages residing in micro- and nanoplastic laden lungs possess transcriptional profiles associated with endocrine system disorders, gastrointestinal disease, and cancers. C_LI

immunology↗

bioRxiv2025

CDKN2ALow cancer cells outcompete macrophages for microenvironmental zinc to drive immunotherapy resistance

Anti-PD1 therapies are primarily thought to rely on functional T cell responses; yet tumors with limited T cell infiltration can still benefit, suggesting alternative mechanisms contribute to therapeutic efficacy. Indeed, we found that myeloid-rich, T cell-poor tumor models respond to anti-Pd1, and this is dependent on a cancer cell-macrophage crosstalk mediated by cancer cell Cdkn2a expression. Mechanistically, we found that cancer cells with decreased Cdkn2a expression (Cdkn2aLow), which occurs in [~]50% of all human cancers, reorganize zinc compartmentalization by upregulating the zinc importer Slc39a9 at the plasma membrane. Increased cancer cell plasma membrane Slc39a9 leads to intracellular zinc accumulation in cancer cells and depletion of zinc in the tumor microenvironment (TME), resulting in zinc-starved tumor-associated macrophages (TAMs) with reduced phagocytic activity. Restoring zinc availability in TAMs--via dietary supplementation or Slc39a9 knockdown in cancer cells--reprograms TAMs to a pro-phagocytic state and sensitizes Cdkn2aLow tumors to anti-Pd1 therapy. Remarkably, Slc39a9 knockdown tumors respond to anti-Pd1 in Rag1-/- mice, and co-injection of zinc-replete macrophages is sufficient to drive an anti-Pd1 response in immunodeficient mice, demonstrating the T cell-independent nature of this response. Clinically, TAMs from CDKN2ALow cancer patients show reduced zinc and phagocytosis gene signatures. Moreover, patients with lower circulating zinc levels have significantly worse time-to-event outcomes than those with higher levels. Together, these findings uncover a previously unrecognized mechanism by which Cdkn2aLow cancer cells outcompete TAMs for zinc, impairing their function and limiting anti-Pd1 efficacy. They also provide evidence that macrophages alone, without T cells, can enhance anti-PD1 response through zinc-mediated reprogramming of phagocytosis.

cancer biology↗

bioRxiv2019

Metastatic breast cancers have reduced immune cell recruitment but harbor increased macrophages relative to their matched primary tumors

The interplay between the immune system and tumor progression is well recognized. However, current human breast cancer immunophenotyping studies are mostly focused on primary tumors with metastatic breast cancer lesions remaining largely understudied. To address this gap, we examined exome-capture RNA sequencing data from 50 primary breast tumors (PBTs) and their patient-matched metastatic tumors (METs) in brain, ovary, bone and gastrointestinal tract. We used gene expression signatures as surrogates for tumor infiltrating lymphocytes (TIL) and compared TIL patterns in PBTs and METs. Enrichment analysis and deconvolution methods both revealed that METs have a significantly lower abundance of total immune cells, including CD8+ T cells, regulatory T cells and dendritic cells. An exception was M2-like macrophages, which were significantly higher in METs across the organ sites examined. Multiplex immunohistochemistry results were consistent with data from the in-silico analysis and showed increased macrophages in METs. We confirmed the finding of a significant reduction in immune cells in brain (BRM) METs by pathologic assessment of TILs in a set of 49 patient-matched pairs of PBT/BRMs. These findings indicate that METs have an overall lower infiltration of immune cells relative to their matched PBTs, possibly due to immune escape. RNAseq analysis suggests that the relative levels of M2-like macrophages are increased in METs, and their potential role in promoting breast cancer metastasis warrants further study.

immunology↗