Amygdala metabolic activity on [ 18 F]FDG PET is associated with survival, response to immune checkpoint inhibition, and tumor immune signaling in non-small cell lung cancer
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Amygdala metabolic activity (AmygAc) measured by [ 18 F]FDG PET has been associated with chronic psychological stress and adverse clinical outcomes, but its relationship with antitumor immunity and treatment response remains incompletely understood. We investigated AmygAc as a host-derived imaging biomarker in non-small cell lung cancer (NSCLC) and examined its association with survival, response to immune checkpoint inhibition (ICI), and the tumor immune microenvironment. Methods In this multicenter retrospective study, baseline [ 18 F]FDG PET scans from 256 treatment-naïve patients with NSCLC were analyzed to quantify AmygAc. Overall survival was assessed in the full cohort, and treatment response was evaluated in 79 patients who subsequently received neoadjuvant ICI therapy. AmygAc was integrated with clinical and tumor-derived imaging parameters. To investigate its biological correlates, tumor tissue from a selected subcohort was analyzed using multiplex immunofluorescence and spatial transcriptomics. Results Higher AmygAc was associated with poorer survival and remained independently associated with outcome after multivariable adjustment for established clinical and imaging parameters. Among patients receiving neoadjuvant ICI therapy, AmygAc was lower in responders than in non-responders (0.76 vs. 0.81, *P* = 0.003) and discriminated treatment response with an area under the receiver operating characteristic curve of 0.80. Molecular profiling demonstrated attenuated interferon-γ signaling in tumors from patients with higher AmygAc (normalized enrichment score = −1.65; false discovery rate = 0.015). Multiplex immunofluorescence further showed a non-significant trend toward reduced cytotoxic T-cell infiltration together with significantly increased spatial proximity of cytotoxic T cells to PD-L1-expressing cells, without corresponding differences in overall PD-L1 expression. Conclusions AmygAc derived from routine [ 18 F]FDG PET is a host-derived imaging biomarker associated with survival, ICI response, and distinct features of the tumor immune microenvironment in NSCLC. These findings link neural metabolic activity with antitumor immune regulation and support prospective evaluation of AmygAc as a complementary biomarker for risk stratification and immunotherapy response.
Authors: Barbara Katharina Geist, Chrysoula Vraka, Clara T.S. Mertel, Lucian Beer, Armin Frille, Laurin Herbsthofer, Nadine Hermann, Swen Hesse, Lukas Kenner, Daria Kifjak, Kilian Kluge, Oana Cristina Kulterer, Constantin Lapa, Alessandro Lieblich, Thomas Selim Nakuz, Felicitas Oberndorfer, Renate Kain, Helmut Prosch, Osama Sabri, Bernhard Sattler, Thomas Schweiger, Clemens Aigner, Clemens Spielvogel, Dato Tsomaia, Karolina Trachtova, Martina Tomberger, Hubert Wirtz, Josef Yu, Stefan Grünert, Marcus Hacker
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7212432634