Abstract LB374: Chronic emotional distress in lung cancer is associated with attenuated IFN-gamma-signaling and dysfunctional T cells, diminished response to immune checkpoint blockade and adverse outcome
Authors: Barbara Katharina Geist, Chrysoula Vraka, Thomas Selim Nakuz, Karolina Trachtova, Song Xue, Chengcheng Shi, Kilian Kluge, Oana Kulterer, Josef Yu, Laurin Herbsthofer, Alessandro Liebich, Martina Tomberger, Thomas Schweiger, Helmut Prosch, Felicitas Oberndorfer, Constantin Lapa, Xinli Xie, Hong Zong, Lukas Kenner, Stefan Gruenert, Marcus Hacker
Journal: Cancer Research (2025)

Abstract Introduction: There is accumulating evidence that chronic mental stress leads to immune checkpoint inhibitor (ICI) therapy resistance and negatively impacts outcome in cancer patients, but molecular mechanisms remain elusive. Experimental procedures: In two retrospective lung cancer cohorts we assessed amygdala status as primary marker for chronic stress, tumor parameters and bone marrow activation by whole body [18F]FDG-PET at initial diagnosis. In C1 194 lung cancer patients receiving traditional therapies were followed for 85.5 months and in C2 60 lung cancer patients receiving ICI-therapy in the first line were assessed for therapy response using the Junker scoring system. Subjects were dichotomized into chronic and low stress, based on amygdalar activity. Tumor volumes were delineated semi-automatically and TLG served as marker of tumor metabolic activity and FDG uptake in the bone marrow was normalized to blood pool activity. For molecular analysis twenty bio-banked tissue samples were used for full genomic sequencing, spatial analysis of tumor tissue was performed using multiplexed immunohistochemistry and spatial transcriptomics (10xgenomics). Results: Univariate regression analysis identified the primary stress marker (P &amp;lt; 0·001*) predict a death event within 1 year. Moreover, chronic stress correlated significantly with bone marrow (r = 0·24, P = 0·001*) and CRP (r = 0·21, P = 0·006*), but not with TLG (r = 0·1). Multi-omics analysis of 20 therapy naïve tumor samples identifies chronic stress attenuates in the tumor tissue IFN-γ signaling (P = 0·01, NES = -1·58) and the tumor microenvironment harbours a reduced number of cytotoxic T cells, which are however more frequently in the vicinity of PD-L1 expressing cells (P = 0·009*). A mediation analysis confirmed the direct effect (4.1, P = 0.008*) between the primary stress measure and one-year survival, and also a statistically significant indirect effect (0.5, P &amp;lt; 0.05*), showing that the relation was serially mediated via (i) inflammation and (ii) TLG. In C2 68% of patients with ICI therapy showed a complete or almost complete pathological response (Junker 2b or Junker 3), while 32% had a response of Junker 2a or worse. While among the non-responding patients 60% displayed the stress marker high AmygAc, only 13% of the responders were chronically stressed. Conclusion: We show that therapy naïve lung cancer patients can be stratified by [18F]FDG amygdalar activity into chronically stressed individuals with lower life expectancy (C1) and ICI-therapy resistance (C2). The TME in these patients lacks IFN-γ signaling and activated T cells in the tumor, which we propose as molecular mechanism mediating the stress induced bad outcome. Citation Format: Barbara Katharina Geist, Chrysoula Vraka, Thomas Selim Nakuz, Karolina Trachtova, Song Xue, Chengcheng Shi, Kilian Kluge, Oana Kulterer, Josef Yu, Laurin Herbsthofer, Alessandro Liebich, Martina Tomberger, Thomas Schweiger, Helmut Prosch, Felicitas Oberndorfer, Constantin Lapa, Xinli Xie, Hong Zong, Lukas Kenner, Stefan Gruenert, Marcus Hacker. Chronic emotional distress in lung cancer is associated with attenuated IFN-gamma-signaling and dysfunctional T cells, diminished response to immune checkpoint blockade and adverse outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB374.