Biology subjects

Leatherman, J.

Publications and source records attributed to Leatherman, J..

4 recordsLinked to original sources

bioRxiv2025

Antigen-presenting cancer-associated fibroblasts in murine pancreatic tumors differentially control regulatory T cell phenotype and function via CXCL9 and CCL22

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a complex tumor microenvironment (TME) including stromal cells that influence resistance to therapy. Recent studies have revealed that stromal cancer-associated fibroblasts (CAFs) are heterogeneous in origin, gene expression, and function. Antigen-presenting CAFs (apCAFs), are defined by major histocompatibility complex (MHC)-II expression and can activate effector CD4+ T cells that have the potential to contribute to the anti-cancer immune response, but also can induce regulatory T cell (Treg) differentiation. Whether apCAFs promote or restrain the antitumor response remains uncertain. Using tumor clones of the KPC murine PDAC model differing in sensitivity to immune checkpoint blockade (ICB), we found that immunosensitive (sKPC) tumors were characterized by higher immune cell and apCAF infiltration than resistant (rKPC) tumors. IMC analysis showed proximity of apCAFs and CD4+ T cells in both sKPC and rKPC tumors implicating interaction within the TME. apCAF-depleted sKPC tumor-bearing mice had diminished sensitivity to ICB. apCAFs from both sKPC and rKPC tumors activated tumor-infiltrating CD4+ T cells and induced Treg differentiation. However, transcriptomic analysis showed that Tregs induced by apCAFs were overexpressed for immunosuppressive genes in rKPCs relative to sKPCs, and that this is associated with differential chemokine signaling from apCAFs depending on tumor origin. Together these data implicate apCAFs as important mediators of the antitumor immune response, modulation of which could facilitate the development of more effective anti-tumor immune based approaches for PDAC patients.

cancer biology↗

bioRxiv2025

Cancer associated fibroblasts drive epithelial to mesenchymal transition and classical to basal change in pancreatic ductal adenocarcinoma cells with loss of IL-8 expression

Pancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, in part resulting from cellular heterogeneity that supports overall tumorigenicity. Cancer associated fibroblasts (CAF) are key determinants of PDAC biology and response to systemic therapy. While CAF subtypes have been defined, the effects of patient-specific CAF heterogeneity and plasticity on tumor cell behavior remain unclear. Here, multi-omics was used to characterize the tumor microenvironment (TME) in tumors from patients undergoing curative-intent surgery for PDAC. In these same patients, matched tumor organoid and CAF lines were established to functionally validate the impact of CAFs on the tumor cells. CAFs were found to drive epithelial-mesenchymal transition (EMT) and a switch in tumor cell classificiaton from classical to basal subtype. Furthermore, we identified CAF-specific interleukin 8 (IL-8) as an important modulator of tumor cell subtype. Finally, we defined neighborhood relationships between tumor cell and T cell subsets. Statement of SignificanceThis multidimensional analysis highlights the diverse role CAFs have in influencing other cell types in the TME, including epithelial-derived tumor and infiltrating immune cells. Our methods provide a platform for evaluating emerging therapeutic approaches and for studying mechanisms that dictate tumor behavior in a manner that reflects patient-specific heterogeneity.

cancer biology↗

bioRxiv2024

Spatial multi-omics reveal intratumoral humoral immunity niches associated with tertiary lymphoid structures in pancreatic cancer immunotherapy pathologic responders

Pancreatic adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. We generated a spatial multi-omics atlas encompassing 26 PDAC tumors from patients treated with combination immunotherapies. Using machine learning-enabled H&E image classification models and unsupervised gene expression matrix factorization methods for spatial transcriptomics, we characterized cellular states within TLS niches spanning across distinct morphologies and immunotherapies. Unsupervised learning generated a TLS-specific spatial gene expression signature that significantly associates with improved survival in PDAC patients. These analyses demonstrate TLS-associated intratumoral B cell maturation in pathological responders, confirmed with spatial proteomics and BCR profiling. Our study also identifies spatial features of pathologic immune responses, revealing TLS maturation colocalizing with IgG/IgA distribution and extracellular matrix remodeling. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/613714v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@d5e1a5org.highwire.dtl.DTLVardef@1d14012org.highwire.dtl.DTLVardef@c57c6corg.highwire.dtl.DTLVardef@16baa56_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIIntegrated multi-modal spatial profiling of human PDAC tumors from neoadjuvant immunotherapy clinical trials reveal diverse spatial niches enriched in TLS. C_LIO_LITLS maturity is influenced by tumor location and the cellular neighborhoods in which TLS immune cells are recruited. C_LIO_LIUnsupervised machine learning of genome-wide signatures on spatial transcriptomics data characterizes the TLS-enriched TME and associates TLS transcriptomes with survival outcomes in PDAC. C_LIO_LIInteractions of spatially variable gene expression patterns showed TLS maturation is coupled with immunoglobulin distribution and ECM remodeling in pathologic responders. C_LIO_LIIntratumoral plasma cell and immunoglobin gene expression spatial dynamics demonstrate trafficking of TLS-driven humoral immunity in the PDAC TME. C_LI SignificanceWe report a spatial multi-omics atlas of PDAC tumors from a series of immunotherapy neoadjuvant clinical trials. Intratumorally, pathologic responders exhibit mature TLS that propagate plasma cells into malignant niches. Our findings offer insights on the role of TLS-associated humoral immunity and stromal remodeling during immunotherapy treatment.

cancer biology↗

bioRxiv2024

Mimicking the breast metastatic microenvironment: characterization of a novel syngeneic model of HER2+ breast cancer

Preclinical murine models in which primary tumors spontaneously metastasize to distant organs are valuable tools to study metastatic progression and novel cancer treatment combinations. Here, we characterize a novel syngeneic murine breast tumor cell line, NT2.5-lung metastasis (- LM), that provides a model of spontaneously metastatic neu-expressing breast cancer with quicker onset of widespread metastases after orthotopic mammary implantation in immune-competent NeuN mice. Within one week of orthotopic implantation of NT2.5-LM in NeuN mice, distant metastases can be observed in the lungs. Within four weeks, metastases are also observed in the bones, spleen, colon, and liver. Metastases are rapidly growing, proliferative, and responsive to HER2-directed therapy. We demonstrate altered expression of markers of epithelial-to-mesenchymal transition (EMT) and enrichment in EMT-regulating pathways, suggestive of their enhanced metastatic potential. The new NT2.5-LM model provides more rapid and spontaneous development of widespread metastases. Besides investigating mechanisms of metastatic progression, this new model may be used for the rationalized development of novel therapeutic interventions and assessment of therapeutic responses targeting distant visceral metastases SUMMARY STATEMENTWe characterize a new syngeneic, immune-competent murine model of breast cancer (NT2.5-LM) that yields rapid and widespread metastases, preserves spontaneous metastasis, and provides a model for studying novel therapeutic interventions.

cancer biology↗