Peripheral immune signatures associated with peptide receptor radionuclide therapy in neuroendocrine tumors

Background: Peptide receptor radionuclide therapy (PRRT) is an internal radiotherapy for somatostatin receptor (SSTR)-positive neuroendocrine tumor (NET). The tumor microenvironment, particularly cytotoxic T lymphocyte (CTL), is a key determinant of tumor behavior, treatment response, and prognosis, but NET typically shows a “cold” immune microenvironment with sparse immune-cell infiltration, which may contribute to the limited efficacy of ICI-based therapies. External beam radiotherapy can activate systemic antitumor immunity and occasionally induce abscopal effects, in which irradiation of a primary lesion leads to shrinkage of both irradiated and distant metastatic sites; however, the influence of PRRT on systemic immunity has scarcely been studied. We hypothesized that PRRT modulates systemic immunity in NET patients and investigated changes in circulating cytokines. Methods: We analyzed changes in serum cytokine levels in NET patients treated with PRRT at Yokohama City University. Twelve paired serum samples from 9 patients were collected before and after PRRT and analyzed with a 36-plex cytokine array. Results: Of the 9 patients, 7 were undergoing their first PRRT course and 2 a second course (retreatment after a prior four-administration PRRT course that had achieved at least partial response with ≥1.5 year of disease control). Primary sites were pancreas (n=6), rectum (n=1), lung (n=1), and thymus (n=1), and target lesions were in the liver (n=7), bone (n=2), primary site (n=1), lymph node (n=1), and peritoneum (n=1). Twelve serum pairs comprised 10 pre- and post-individual PRRT administrations and 2 pre- and post-full-course pairs. Of the 36 examined cytokines, only 12 were detectable. Among these, CD154 showed more than 2-fold changes in 7 pairs, with 6 showing downregulation and 1 showing upregulation after PRRT. IL-1ra was also upregulated in 3 pairs. Conclusion: We found that PRRT is associated with systemic changes in circulating cytokines in NET patients, notably modulation of CD154 and IL-1ra. These data suggest that PRRT may influence host antitumor immunity; larger studies are required to elucidate the mechanisms and clinical significance of these immune changes.