Biology subjects

Nielsen, S. R.

Publications and source records attributed to Nielsen, S. R..

4 recordsLinked to original sources

bioRxiv2025

Plasminogen activator inhibitors orchestrate the immunosuppressive tumor microenvironment in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense extracellular matrix (ECM) that sustains an immunosuppressive tumor microenvironment (TME). While this protective niche has been described, the molecular determinants orchestrating its formation and dictating its immune interactions are not well defined. Using Perturb-map, we determine how dozens of different gene perturbations shape the growth and cellular environments of PDAC clones through space and time. Our study reveals dynamic, gene-specific adaptations of immune neighborhoods during clonal selection. We identified Serpinb2 (PAI2) and Serpine1 (PAI1) as key cancer-derived mediators of TME remodeling and immune evasion. These factors promote the deposition of a fibrin-rich ECM that shapes immune cell composition, locally retains and polarizes immunosuppressive macrophages and excludes cytotoxic T cells. Deletion of either Serpinb2 or Serpine1 greatly enhanced tumor response to anti-PD1 immunotherapy in an aggressive PDAC model. Transcriptomic analysis further linked their expression to distinct PDAC subtypes and poor patient survival. Our findings demonstrate that Serpinb2 and Serpine1 establish a permissive niche for tumor progression and show how PDAC cells exploit components of the fibrinolysis pathway to remodel the ECM, alter macrophage composition, and protect themselves from immune editing, ultimately reinforcing the role of extracellular factors in shaping an immune-privileged tumor niche.

cancer biology↗

bioRxiv2021

Targeting macrophages with CAR-T cells delays solid tumor progression and enhances anti-tumor immunity

Tumor-associated macrophages (TAMs) are one of the most abundant cell types in many solid tumors and typically exert protumor effects. This has led to an interest in macrophage-depleting agents for cancer therapy, but approaches developed to date have had limited success in clinical trials. Here, we report the development of a strategy for TAM depletion in mouse solid tumor models using chimeric antigen receptor (CAR) T cells targeting the macrophage marker F4/80 (F4.CAR-T). F4.CAR-T cells effectively killed macrophages in vitro and in vivo without toxicity. When injected into mice bearing orthotopic lung tumors, F4.CAR-T cells infiltrated tumor lesions and delayed tumor growth comparably to PD1 blockade, and significantly extended mouse survival. Anti-tumor effects were mediated by F4.CAR-T-produced IFN-{gamma}, which promoted upregulation of MHC molecules on cancer cells and tumor-infiltrating myeloid cells. Notably, F4.CAR-T promoted expansion of endogenous CD8 T cells specific for tumor-associated antigens and led to immune editing of highly antigenic tumor cell clones. Antitumor impact was also observed in mouse models of ovarian and pancreatic cancer. These studies provide proof-of-principle evidence to support CAR-T targeting of TAMs as a means to enhance antitumor immunity.

immunology↗

bioRxiv2021

Perturb-map enables CRISPR genomics with spatial resolution and identifies regulators of tumor immune composition

The cellular architecture of a tumor, particularly immune composition, has a major impact on cancer outcome, and thus there is an interest in identifying genes that control the tumor microenvironment (TME). While CRISPR screens are helping uncover genes regulating many cell-intrinsic processes, existing approaches are suboptimal for identifying gene functions operating extracellularly or within a tissue context. To address this, we developed an approach for spatial functional genomics called Perturb-map, which utilizes protein barcodes (Pro-Code) to enable spatial detection of barcoded cells within tissue. We show >120 Pro-Codes can be imaged within a tumor, facilitating spatial mapping of 100s of cancer clones. We applied Perturb-map to knockout dozens of genes in parallel in a mouse model of lung cancer and simultaneously assessed how each knockout influenced tumor growth, histopathology, and immune composition. Additionally, we paired Perturb-map and spatial transcriptomics for unbiased molecular analysis of Pro-Code/CRISPR lesions. Our studies found in Tgfbr2 knockout lesions, the TME was converted to a mucinous state and T-cells excluded, which was concomitant with increased TGF{beta} expression and pathway activation, suggesting Tgfbr2 loss on lung cancer cells enhanced suppressive effects of TGF{beta} on the TME. These studies establish Perturb-map for functional genomics within a tissue at single cell-resolution with spatial architecture preserved.

immunology↗

bioRxiv2017

Macrophage-derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic cancer

The ability of disseminated cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumour microenvironment that suppresses and/or excludes cytotoxic CD8+ T cells. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease with unmet needs, yet the immuno-protective role of the metastatic tumour microenvironment in pancreatic cancer is not completely understood. In this study we find that macrophage-derived granulin contributes to cytotoxic CD8+ T cell exclusion in metastatic livers. Mechanistically, we find that granulin expression by macrophages is induced in response to colony stimulating factor-1. Genetic depletion of granulin reduces the formation a fibrotic stroma, thereby allowing T cell entry at the metastatic site. While metastatic PDAC tumours are largely resistant to anti-PD-1 therapy, blockade of PD-1 in granulin depleted tumours restored the anti-tumour immune defence and dramatically decreased metastatic tumour burden. These findings suggest that targeting granulin may serve as a potential therapeutic strategy to restore CD8+ T cell infiltration in metastatic PDAC, thereby converting PDAC metastatic tumours, which are refractory to immune checkpoint inhibitors, into tumours that respond to immune checkpoint inhibition therapies.

cancer biology↗