Jablonski, S. A. | Search bioRxiv

bioRxiv2024

Natural killer cells associate with epithelial cells in the pancreatic ductal adenocarcinoma tumor microenvironment

Pancreatic ductal adenocarcinoma (PDAC) exhibits dense fibrosis and immune exclusion. While fibrosis has been studied globally and at the region-of-interest level, its impact on stromal-ductal architecture and immune cell localization remains unknown. Here, we establish cancer-associated fibroblast (CAF)-stratified ductal spatial architecture as a fundamental determinant of immune exclusion in PDAC. Focusing on malignant PDAC epithelial ductal regions, the critical interface where immune cells must access tumor epithelium, we demonstrate that periductal fibroblast organization dictates leukocyte proximity. Through integrative analysis of treatment-naive patient samples from three independent cohorts - including imaging mass cytometry, multiplex immunohistochemistry, and single-cell RNA sequencing - we uncovered that activated, pro-inflammatory leukocytes preferentially localized near malignant ducts in regions with low fibroblast density. Stratifying epithelial-ductal regions by CAF abundance revealed a graded constraint: increasing fibroblast content corresponded to reduced leukocyte-epithelial proximity and elevated collagen I deposition. Despite their exclusion in high-CAF ducts, leukocytes in low-CAF ducts retained functional competence. Mechanistically, ligand-receptor inference implicated collagen-CD44 signaling as an adhesion axis anchoring immune cells within fibroblast-rich zones, with CD44 blockade enhancing natural killer cell invasion and motility in fibrotic spheroid models. Thus, by establishing ductal regions as critical spatial units of immune exclusion, these findings provide a framework for dissecting stromal-immune interactions and reveal targetable "stromal checkpoints" that can be leveraged to overcome CAF-driven barriers to leukocyte motility and infiltration in PDAC. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/593868v3_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@17df874org.highwire.dtl.DTLVardef@142c809org.highwire.dtl.DTLVardef@15af4a7org.highwire.dtl.DTLVardef@74183a_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

Immune Selection Pressure Contributes to Pancreatic Cancer Immune Evasion

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. Pancreatic tumors are minimally infiltrated by T cells and are largely refractory to immunotherapy. Accordingly, the role of T cell immunity in pancreatic cancer has been somewhat overlooked. Here, we hypothesized that immune evasion in pancreatic cancer is induced in response to T cell-based immune selection pressure, and that understanding how pancreatic tumors respond to immune attack may facilitate the development of more effective therapeutic strategies. We now provide the first evidence that T cell-dependent host immune responses induce a PDAC-derived myeloid mimicry phenomenon and stimulate immune evasion. mT3-2D cells derived from a Kras+/LSL-G12D; Trp53+/LSL-R172H; Pdx1-Cre (KPC) mouse model of pancreatic cancer were grown in immunocompetent and immunodeficient C57BL/6 mice, and analyzed to determine the impacts of adaptive immunity specifically on malignant epithelial cells as well as on whole tumors. We found that immune selection pressure, via signal transducer and activator of transcription 1 (STAT1), stimulates malignant epithelial pancreatic cells to induce the expression of genes typically expressed by myeloid cells and alters intratumoral immunosuppressive myeloid cell profiles. Targeting the Janus Kinase (JAK)/STAT signaling pathway using the FDA approved drug, ruxolitinib, overcomes these tumor-protective responses and improves anti-PD1 antibody therapeutic efficacy. These findings provide future directions for treatments that specifically disable this mechanism of resistance in PDAC.

cancer biology↗