Integrin-mediated tumor-stroma interfacial signaling promotes basal-like and immune exclusion phenotype in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a multifaceted disease encompassing various cell types within a dynamic microenvironment. Its pivotal constituents include cancer cells, cancer-associated fibroblasts (CAFs), and macrophages, all of which potentially influence disease progression and resistance to chemoradiotherapy and immunotherapy. Gaining insight into the intricate interactions among these cell types and the regulatory signals governing their behavior is imperative in shaping innovative therapeutic approaches for PDAC. In this study, it was noted that pancreatitis-derived transgenic mice models frequently exhibit a significant immune exclusion in adaptive immune cells, particularly Cd4+, Cd8+ T cells and B cells, but positively correlated with M2 macrophage and neutrophil infiltration. A distinctive transcriptional extracellular matrix (ECM)-receptor signatures enriched with integrin subfamily subunits and their corresponding structural proteins were identified, suggesting a potential association with myofibroblastic cancer-associated fibroblasts (myCAFs) and a negative correlation with NK and CD8+ cell infiltration, while showing a positive correlation with macrophage and neutrophil infiltration. In the ICGC (International Cancer Genome Consortium) datasets, the ECM-receptor signature score of the basal-like subtype was notably higher than that of the classic subtype. Furthermore, patients with higher-risk scores tend to exhibit immune exclusion characteristics and, consequently, a less favorable prognosis. Based on an integrated analysis of single-cell RNA sequencing (scRNA-seq) data, we observed that basal-like cancer cells, myCAFs at the tumor-stromal interface collectively contribute to the ECM molecular signature in mice and human PDACs. Moreover, the spatial association analysis revealed a striking decrease in the quantities of B, NK (Natural killer), CD4+, and CD8+ T cells within tissue slides that exhibited a high concentration of spatial transcriptomic (ST) spots enriched with the ...