July 2026
Autotaxin-Mediated Suppression of Eosinophils Promotes Pancreatic Cancer Progression
Article: Autotaxin–lysolipid signaling suppresses a CCL11–eosinophil axis to promote pancreatic cancer progression
Bhattacharyya S, Oon C, Diaz L, et al.
Nat Cancer. 2024
Reviewed by Alessandro Vrenna, University of Brescia, Brescia, Italy
Emerging evidence for the antitumor activity of eosinophils in solid tumors motivated Bhattacharyya et al. to investigate the role of autotaxin (ATX)-derived lysophosphatidic acid (LPA) in regulating the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Read more
The authors examined eosinophil-recruiting chemokines in PDAC cells following genetic and pharmacologic inhibition of ATX, finding that CCL11 (eotaxin-1) was selectively upregulated. As the c-Jun transcription factor regulates CCL11 expression in other cellular contexts, they further assessed c-Jun phosphorylation and nuclear localization, concluding that ATX-LPA signaling represses c-Jun activity in PDAC cells.
The study then linked this pathway to tumor biology by showing that increased eosinophil infiltration was associated with greater PDAC cell apoptosis, whereas eosinophil depletion promoted metastatic spread. These findings support a functional link between ATX activity, suppression of CCL11, reduced eosinophil recruitment and PDAC tumor progression. To translate these findings to human disease, the authors observed that higher eosinophil density in PDAC tissue samples was associated with improved overall survival.
Overall, this is a robust and interesting study. The use of both genetic and pharmacological ATX inhibition strengthens the causal link between ATX activity and CCL11-mediated eosinophil infiltration, and highlights the role of eosinophils in tumor suppression. However, some important questions remain unresolved. In particular, the downstream mechanisms by which eosinophils mediate tumor suppression or the impact of ATX inhibition on other immune populations in the PDAC microenvironment. In addition, the primary mechanistic findings were observed in mouse models, which may not fully recapitulate human PDAC.
Although this study highlights the contributions of CCL11 to eosinophil migration in PDAC, the current literature on cancer-signaling remains limited and has more commonly described LPA as an activator of JNK/AP-1/c-Jun signaling (Oyesanya, RA et al. Mol Cancer (2010). https://doi.org/10.1186/1476-4598-9-8; Malchinkhuu, E et al. Oncogene (2005). https://doi.org/10.1038/sj.onc.1208805). Further research is needed to clarify the context-dependent mechanisms governing eosinophil infiltration into neoplastic tissue and their pro- or anti-tumorigenic functions across distinct tumor microenvironments.
Alessandro Vrenna is an MD–PhD trainee in Allergology and Clinical Immunology at the University of Brescia. Their research focuses on hymenoptera venom and drug allergies, severe asthma, chronic rhinitis, and eosinophilic disorders, including Eosinophilic Esophagitis and Eosinophilic Granulomatosis with Polyangiitis. They are currently an investigator for Severe Asthma Network Italy (SANI) and a multicenter study on asthma phenotyping.