Abstract 2516: Loss of cadherin 11 in pancreatic cancer induces altered immune cell infiltration

Abstract 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. Preclinical murine models have been developed that leverage key driver mutations and have significantly contributed to our understanding of PDAC. One such genetically engineered mouse model (GEMM) that has emerged as an important tool is the KPC mouse (LSL-KrasG12D/+;LSL-Trp53R172H/+; p48-Cre) that spontaneously develops pancreatic tumors at ~14-16 weeks of age. Cadherin-11 (Cdh11), a cell-to-cell adhesion molecule has been suggested to play a role in development of the desmoplastic stroma in PDAC, that leads to difficulties in drug accessibility and has been hypothesized to contribute to chemotherapeutic resistance and correlate with poor prognosis. However, the mechanisms by which Cdh11 deficiency in the stromal microenvironment of PDAC-bearing KPC mice influences tumor infiltrating immune cells, has yet to be fully understood. Single-cell RNA sequencing (scRNAseq) of the immune (CD45+) compartment of tumor bearing Cdh11 proficient (KPC/Cdh11+/+), tumor bearing Cdh11 deficient (KPC/Cdh11+/-), non-tumor bearing Cdh11 deficient (Cdh11+/-) and wildtype (Cdh11+/+) mice was performed. We observed a sharp decrease in the presence of myeloid/monocyte lineage cells (CD14+) in KPC/Cdh11+/- tumors and also an increase in T, B and plasma cells, compared to KPC/Cdh11+/+ tumors. Genes upregulated in infiltrating T- and NK cells specific to a Cdh11 deficient background include Cd8a, Nkg7, Maf. Additionally, genes found to be upregulated in B cell clusters in Cdh11 deficient mice include those related to B cell differentiation/activation such as Lgals1, Id2, Itgb1, Rgs1. The increase in B and T cell infiltration was specific to the Cdh11 deficient background, since both pancreata from KPC/Cdh11+/+and Cdh11+/- mice had elevated levels of infiltration. Immunohistochemical validation of these findings has confirmed these changes in tumor infiltrating immune cells. Additionally of note, an increase in antibody-producing plasma cells was observed specifically in a Cdh11 deficient background. Igkc, an immunoglobulin found to be enriched in plasma cells was highly expressed in this group of immune cells. We also observed that KPC/Cdh11+/-had significantly more Igkc expressing cells than KPC/Cdh11+/+. Future work is needed to clearly define the role of Cdh11 in modulating B, T and plasma cell behavior and subsequent contributions to PDAC outcome. This study received funding by LDRD 19-SI-003. This work was conducted under the auspices of the USDOE by LLNL (DE-AC52-07NA27344), LLNL-ABS-820889. This work was supported by AACR-AstraZeneca Fellowship in Immunooncology Research, grant 17-40-12-PERA; The Ruesch Center for the Cure of Gastrointestinal Cancers grant award; NIH R01 CA170653; and NIH Cancer Center Support Grant P30 CA051008. Citation Format: Kelly A. Martin, Aimy Sebastian, Nicholas Hum, Ivana Peran, Stephen Byers, Elizabeth Wheeler, Matthew Coleman, Gabriela Loots. Loss of cadherin 11 in pancreatic cancer induces altered immune cell infiltration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2516.