Background
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy, largely due to its high rate of early metastasis. PDAC remains almost uniformly refractory to T cell-based immunotherapies that have transformed treatment in many other cancers, and there is a critical need to identify new therapeutic approaches. The abundance and functions of eosinophils in PDAC have not been explored despite increasing evidence for important roles of eosinophils in other tumor types. Here, we quantified tumor eosinophilia in preclinical PDAC models and a large PDAC patient cohort, and we assessed whether modulation of eosinophils impacts primary tumor growth or metastasis. 

Methods
We used flow cytometry and immunohistochemistry to quantify eosinophil abundance in PDAC patient samples and in subcutaneous, orthotopic, and genetically engineered mouse models (GEMMs) of PDAC. We used single cell RNA-sequencing (scRNA-seq) and cytokine arrays to study the mechanism by which eosinophils are recruited into pancreatic tumors. Using an eosinophil-deficient mouse model (dblGATA), genetically engineered cytokine-overexpressing cell lines, and systemic injection of exogenous interleukin-33 (IL-33), we studied the effects of eosinophil depletion, expansion, and activation on primary tumor growth and metastasis in murine PDAC. We used scRNA-seq to study mechanisms by which intratumoral eosinophils may impact PDAC metastasis. 

Results
Eosinophils were abundant in PDAC samples from human patients and murine models. They are likely recruited into tumors via 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 spontaneous lung metastases. Treating mice with recombinant IL-33 expands eosinophils systemically and reduces rates of metastasis. Wild-type and eosinophil-deficient mice have similar metastasis burdens after intravenous injection of tumor cells, suggesting that eosinophils do not limit metastasis by impacting the pre-metastatic niche. Rather, eosinophils may interact with other intratumoral cell types to limit the entry of cancer cells into circulation. Indeed, scRNA-seq reveals that eosinophil deficiency is associated with a significant shift in the proportions of intratumoral endothelial cell (EC) subpopulations from tip-like to stalk-like ECs. 

Conclusion
Eosinophils are recruited by locally produced cytokines into the PDAC TME, where they shape the endothelial compartment and regulate the metastatic spread of tumor cells. Further studies are warranted to better delineate the mechanisms underlying this phenotype and to determine whether tumor eosinophilia can serve as a useful therapeutic target or prognostic biomarker in PDAC patients.

Eosinophils regulate metastasis in pancreatic cancer

 Hematology / Oncology / Pathology

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Eosinophils regulate metastasis in pancreatic cancer

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