Taste-immune associative learning amplifies immunopharmacological effects and attenuates disease progression in a rat glioblastoma model

Susann Hetze; Lennart Barthel; Laura Lückemann; Hauke S Günther; Clemens Wülfing; Yasmin Salem; Marie Jakobs; Tina Hörbelt-Grünheidt; Jasmin Petschulat; Ivo Bendix; Ulrike Weber-Stadlbauer; Ulrich Sure; Manfred Schedlowski; Martin Hadamitzky

doi:10.1016/j.bbi.2022.09.006

Taste-immune associative learning amplifies immunopharmacological effects and attenuates disease progression in a rat glioblastoma model

Brain Behav Immun. 2022 Nov:106:270-279. doi: 10.1016/j.bbi.2022.09.006. Epub 2022 Sep 14.

Affiliations

¹ Department of Neurosurgery, University Hospital Essen, University of Duisburg-Essen, Germany; Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- Behavioral Sciences (C-TNBS), University Hospital Essen, University Duisburg-Essen, Germany. Electronic address: [email protected].
² Department of Neurosurgery, University Hospital Essen, University of Duisburg-Essen, Germany; Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- Behavioral Sciences (C-TNBS), University Hospital Essen, University Duisburg-Essen, Germany.
³ Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- Behavioral Sciences (C-TNBS), University Hospital Essen, University Duisburg-Essen, Germany.
⁴ Group for Interdisciplinary Neurobiology and Immunology (INI)-RESEARCH, University of Hamburg, Germany.
⁵ Department of Pediatrics I/ Experimental Perinatal Neurosciences, University Hospital Essen, University of Duisburg-Essen, Germany.
⁶ Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.
⁷ Department of Neurosurgery, University Hospital Essen, University of Duisburg-Essen, Germany.
⁸ Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- Behavioral Sciences (C-TNBS), University Hospital Essen, University Duisburg-Essen, Germany; Department of Clinical Neuroscience, Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm, Sweden.
⁹ Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- Behavioral Sciences (C-TNBS), University Hospital Essen, University Duisburg-Essen, Germany. Electronic address: [email protected].

PMID: 36115545
DOI: 10.1016/j.bbi.2022.09.006

Abstract

Mechanistic target of rapamycin (mTOR)-signaling is one key driver of glioblastoma (GBM), facilitating tumor growth by promoting the shift to an anti-inflammatory, pro-cancerogenic microenvironment. Even though mTOR inhibitors such as rapamycin (RAPA) have been shown to interfere with GBM disease progression, frequently chaperoned toxic drug side effects urge the need for developing alternative or supportive treatment strategies. Importantly, previous work document that taste-immune associative learning with RAPA may be utilized to induce learned pharmacological placebo responses in the immune system. Against this background, the current study aimed at investigating the potential efficacy of a taste-immune associative learning protocol with RAPA in a syngeneic GBM rat model. Following repeated pairings of a novel gustatory stimulus with injections of RAPA, learned immune-pharmacological effects could be retrieved in GBM-bearing animals when re-exposed to the gustatory stimulus together with administering 10 % amount of the initial drug dose (0.5 mg/kg). These inhibitory effects on tumor growth were accompanied by an up-regulation of central and peripheral pro-inflammatory markers, suggesting that taste-immune associative learning with RAPA promoted the development of a pro-inflammatory anti-tumor microenvironment that attenuated GBM tumor growth to an almost identical outcome as obtained after 100 % (5 mg/kg) RAPA treatment. Together, our results confirm the applicability of taste-immune associative learning with RAPA in animal disease models where mTOR overactivation is one key driver. This proof-of-concept study may also be taken as a role model for implementing learning protocols as alternative or supportive treatment strategy in clinical settings, allowing the reduction of required drug doses and side effects without losing treatment efficacy.

Keywords: Associative learning; Dose reduction; Glioblastoma; Rapamycin; Tumor microenvironment; mTOR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Progression
Glioblastoma* / drug therapy
Glioblastoma* / pathology
Rats
Sirolimus / pharmacology
TOR Serine-Threonine Kinases
Taste
Tumor Microenvironment

Substances

TOR Serine-Threonine Kinases
Sirolimus