Cancer Associated Thrombosis Alters Innate Immune Cells (Neutrophils) to Promote Pancreatic Ductal Adenocarcinoma (PDAC) Progression

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Presentation Time: 05:15 PM - 05:30 PM
Abstract ID: 5692 - B

Presenting Author:
Asha Thomas , Postdoctoral Scholar at Case Western Reserve Univ. Sch. of Med.

Abstract:

The high incidence of Cancer Associated Thrombosis (CAT) in PDAC contributes to its poor prognosis and high mortality. It is unclear how CAT affects subsequent cancer progression. Given innate immune system’s role in CAT and cancer, we posited that neutrophils are altered by CAT to facilitate tumor growth. Murine PDAC cell line PAN02 was injected subcutaneously or orthotopically to WT mice, and thrombosis was induced after a week by IVC ligation or retroorbital microbeads injection. Mice with CAT developed significantly larger tumors vs. mice with only tumor. Neutrophil depletion with antiLy6G antibody or S100A8^+/+/iDTR^+/+ mouse model abrogated increased tumor growth in CAT mice. In PAN02 mice, neutropenia instead resulted in increased tumor growth indicating CAT changes neutrophil phenotype from antitumor to protumor. Analysis of immune cells in TME by flow cytometry/IHC showed less CD8⁺T-cell populations in CAT mice. Though TANs from PDAC+CAT caused significant increase in apoptosis of CD8⁺T cells this couldn’t fully explain the reduction of CD8⁺T cells in the CAT tumors. RNA-seq of circulating neutrophils of PDAC vs. PDAC+CAT showed alterations in hypoxia and inflammasome pathways. Future studies will explore molecular mechanisms of CAT-directed neutrophil and TME alterations. Our novel results show that CAT alters neutrophil activity which affects TME facilitating tumor growth. These results have the potential to create a paradigm shift in the disease management.