Peripheral Immune Signatures Related to Peptide Receptor Radionuclide Therapy in Neuroendocrine...

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. Citation Format: Eriko Katsuta, Takuto Nobuhiro, Masaru Takeuchi, Satoshi Matsui, Asano Daisuke, Ishikawa Yoshiya, Hiroki Ueda, Keiichi Akahoshi, Noritoshi Kobayashi, Yasushi Ichikawa, Daisuke Ban. Peripheral immune signatures associated with peptide receptor radionuclide therapy in neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7754.