AUTHOR=Sebastian Aimy , Martin Kelly A. , Peran Ivana , Hum Nicholas R. , Leon Nicole F. , Amiri Beheshta , Wilson Stephen P. , Coleman Matthew A. , Wheeler Elizabeth K. , Byers Stephen W. , Loots Gabriela G. 

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

JOURNAL=Frontiers in Oncology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1286861

DOI=10.3389/fonc.2023.1286861

ISSN=2234-943X

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