Loss of Cadherin-11 in pancreatic ductal adenocarcinoma alters tumor-immune microenvironment

• DOI: 10.3389/fonc.2023.1286861
• Publication Date: 2023-10-26T23:05:01Z
• Authors: Aimy Sebastian; Kelly A. Martin; Ivana Peran; Nicholas R. Hum; Nicole F. Leon; Beheshta Amiri; Stephen P. Wilson; Matthew A. Coleman; Elizabeth K. Wheeler; Stephen W. Byers; Gabriela G. Loots
• Keywords: CDH11; Biomedical and Clinical Sciences; Oncology and Carcinogenesis; Immunology; MDSC; T cells; 610; PDAC; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Clinical sciences; Oncology and carcinogenesis; 3. Good health; Pancreatic Cancer; Orphan Drug; Rare Diseases; Oncology; 2.1 Biological and endogenous factors; IL33; Immunotherapy; Aetiology; CAF; Digestive Diseases; RC254-282; Cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the top five deadliest forms cancer with very few treatment options. The 5-year survival rate for PDAC 10% following diagnosis. Cadherin 11 (Cdh11), a cell-to-cell adhesion molecule, has been suggested to promote tumor growth and immunosuppression in PDAC, Cdh11 inhibition significantly extended mice PDAC. However, mechanisms by which deficiency influences progression anti-tumor immune responses have yet be fully elucidated. To investigate -deficiency induced changes microenvironment (TME), we crossed p48-Cre; LSL-Kras G12D/+ ; LSL-Trp53 R172H/+ (KPC) +/- performed single-cell RNA sequencing (scRNA-seq) non-immune (CD45 - ) + compartment KPC tumor-bearing proficient ( KPC-Cdh11 +/+ deficient mice. Our analysis showed that expressed primarily cancer-associated fibroblasts (CAFs) at low levels epithelial cells undergoing epithelial-to-mesenchymal transition (EMT). altered molecular profile CAFs, leading decrease expression myofibroblast markers such as Acta2 Tagln cytokines Il6 , Il33 Midkine (Mdk) . We also observed significant presence monocytes/macrophages neutrophils tumors while proportion T was increased. Additionally, myeloid lineage from -deficient had reduced immunosuppressive previously shown play role suppression. In summary, our data suggests alters fibroblast microenvironments contributes reduction cytokines, an increase immunity enhanced survival.