Biology subjects

Tlsty, T.

Publications and source records attributed to Tlsty, T..

3 recordsLinked to original sources

bioRxiv2025

A fibroblast-centric network drives cold fibrosis in the tumor microenvironment of lung squamous cell carcinoma

The tumor microenvironment (TME) of chronic inflammation-associated cancers (CIACs) is shaped by cycles of injury and maladaptive repair, yet the principles organizing fibrotic stroma in these tumors remain unclear. Here, we applied the concept of hot versus cold fibrosis, originally credentialed in non-cancerous fibrosis of heart and kidney, to lung squamous cell carcinoma (LUSC), a prototypical CIAC. Single-cell transcriptomics of matched tumor and adjacent-normal tissue from 16 treatment-naive LUSC patients identified a cold fibrotic architecture in the LUSC TME: cancer-associated fibroblasts (CAFs) expanded and adopted myofibroblast and stress-response states, while macrophages were depleted. This macrophage-poor, CAF-rich stroma was maintained by CAF autocrine growth factor loops, including TIMP1, INHBA, TGFB1, and GMFB. In parallel, the immune compartment exhibited a hot tumor phenotype with abundant T and B cells, forming spatially distinct but molecularly engaged networks with CAFs. CAF gene programs typifying cold fibrosis in LUSC were conserved in other CIACs, including esophageal and gastric adenocarcinomas. These results redefine desmoplastic regions of tumors through the lens of a non-cancer fibrosis model, demonstrating that conserved stromal circuits constitute therapeutic vulnerabilities in CIACs.

cancer biology↗

bioRxiv2025

Blocking Osteoprotegerin Reprograms Cancer Associated Fibroblast to Promotes Immune Infiltration into the Tumor Microenvironment

AbstractThe stromal compartment of many solid tumors plays a critical role in shaping an immunosuppressive microenvironment that limits the effectiveness of immune-based therapies1. Among stromal constituents, cancer-associated fibroblasts (CAFs) have emerged as key regulators of antitumor immunity2-5. Here, we identify a distinct subset of CAFs in both murine and human stroma-rich cancers that secrete osteoprotegerin (OPG)-- a soluble decoy receptor that neutralizes receptor activator of nuclear factor kappa-B ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL), both of which are involved in T cell function. In vitro, OPG directly impairs CD8 T cell-mediated killing of target cells. In murine models of pancreatic and breast cancer, antibody-mediated blockade of OPG promotes robust immune infiltration into the tumor microenvironment, leading to significant tumor regression. Stromal profiling revealed that OPG blockade induces a shift in CAF cells--reducing immunosuppressive OPG fibroblasts while expanding interferon-responsive fibroblasts, thus recalibrating the tumor stroma toward a pro-immunogenic landscape. These findings uncover a previously unrecognized mechanism of stromal immune suppression and highlight OPG as a stromal immune checkpoint controlling CD8 T cell infiltration. Targeting OPG may offer a novel therapeutic strategy to convert immunologically "cold" tumors into T cell-infiltrated, tumor microenvironment.

cancer biology↗

bioRxiv2022

Antigen-dependent inducible T cell reporter system for PET imaging of breast cancer and glioblastoma

For the past several decades, chimeric antigen receptor T cell (CAR T) therapies have shown promise in the treatment of cancers. These treatments would greatly benefit from companion imaging biomarkers to follow the trafficking of T cells in vivo. Using synthetic biology, we engineered T cells with a chimeric receptor SyNthetic Intramembrane Proteolysis Receptor (SNIPR) that induces overexpression of an exogenous reporter gene cassette upon recognition of specific tumor markers. We then applied a SNIPR-based positron emission tomography (PET) reporter system to two cancer-relevant antigens, human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor variant III (EGFRvIII), commonly expressed in breast and glial tumors respectively. Antigen-specific reporter induction of the SNIPR-PET T cells was confirmed in vitro using GFP fluorescence, luciferase luminescence, and the HSV-TK PET reporter with [18F]FHBG. T cells associated with their target antigens were successfully imaged using PET in dual xenograft HER2+/HER2- and EGFRvIII+/EGFRvIII-animal models, with > 10-fold higher [18F]FHBG signals seen in antigen-expressing tumors versus the corresponding controls. The main innovation described is therefore PET detection of T cells via specific antigen-induced signals, in contrast to reporter systems relying on constitutive gene expression.

synthetic biology↗