IL-33 as a Marker of Poor Early Response in Neuroendocrine Tumor Patients Undergoing Peptide Receptor Radionuclide Therapy

Despite a high disease control rate in the treatment of unresectable or metastatic well-differentiated, somatostatin receptor-positive neuroendocrine tumors (NETs) with peptide receptor radionuclide therapy (PRRT), a certain percentage of patients will experience an unfavorable outcome. Besides clinical, hematological, and biochemical parameters, including widely used inflammatory markers, as well as literature-recognized inflammatory indices, there is a growing need for the identification of novel biomarkers as prognostic factors of therapeutic response. In this prospective single-center study, 51 NET patients treated with PRRT were included and divided into two groups: responders and non-responders in accordance with therapeutic outcome. Cytokine, clinical, and biochemical data were analyzed. Non-responders had significantly higher serum concentrations of IL-33 and IL-4 in comparison to responders, while sST2 was increased in responders. A positive correlation was measured between IL-33 and IL-4, as well as between IL-33 and disease progression. A negative correlation was noted between IL-33 and the neutrophil count %. ROC curve analysis identified values of IL-33 >146.5 pg/mL as a predictor of poor early therapeutic response, and logistic regression confirmed its independent prognostic value. Elevated IL-33 and IL-4 favor the development of a type 2 immune response associated with unfavored therapeutic outcome, while increased sST2 mitigates the IL-33's effect in responders, contributing to a more favorable response. These findings emphasize IL-33 as an important biomarker of early response in NET patients undergoing PRRT.