Investigating the impact of eosinophils on pancreatic cancer growth and metastasis

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies, largely due to its high rate of early metastasis to the liver, lung, and other distant sites. While T cell-based immunotherapies have shown promise in many other cancers, PDAC remains almost uniformly refractory to these therapeutic approaches. We identified eosinophils as a prominent component of the PDAC tumor microenvironment (TME) in both human patients and murine models. Eosinophils are likely recruited into the tumor due to the local production of eotaxin-1 and eotaxin-2 by distinct populations of cancer associated fibroblasts and macrophages. Eosinophil expansion or depletion does not impact the growth of primary pancreatic tumors, but mice lacking eosinophils are more likely to develop lung metastases after complete resection of primary tumors. Treating mice with recombinant IL-33 expands eosinophils systemically and leads to a reduction in metastasis. Wild-type and eosinophil-deficient mice have similar burdens of lung metastasis after intravenous injection of tumor cells, suggesting that eosinophils do not limit metastasis by impacting the pre-metastatic niche. Rather, eosinophils may act at the site of the primary tumor to limit the ability of cancer cells to enter or survive in circulation. Single cell RNA-sequencing analysis of primary murine PDAC shows that eosinophil deficiency does not skew the immune composition of the TME but is associated with the emergence of a distinct fibroblast subpopulation characterized by overexpression of TGFβ family signaling molecules (e.g. Tgfb1/2, Inhba, Tgfbr1/2, and Smad3/4/5), WNT pathway modulators (e.g. Tnks, Tnks2, Slc30a9), and extracellular matrix proteins previously implicated in metastasis (e.g. tenascin-C and perlecan). In summary, tumor eosinophils in PDAC shape the microenvironment and limit metastatic spread without impacting primary tumor growth.