Role of microglia in neurological side effects of cancer immunotherapies and of ruxolitinib in steroid-refractory gastrointestinal graft versus host disease

Abstract: Immunological therapies such as checkpoint-inhibitor therapy (ICI) and CAR T cell therapy revolutionised the field of cancer treatment. Unfortunately, they are bound to invalidating neurological side effects. In this thesis we aimed to describe the role of microglia in neurological side effects of ICI (n-irAE) and in immune effector cell-associated neurotoxicity syndrome (ICANS). In a preclinical model of n-irAEs, microglia were higher in number in the brain cortex, assumed a morphologically active conformation and expressed a higher level of activation markers such as CD80 and MHC II upon treatment with anti-PD1 antibody compared to controls. Interestingly, microglia-depleted, and not T cell-depleted mice experienced less neurocognitive deficits compared to controls. Moreover, we were able to find a trend towards microglia activation in brain biopsies and higher levels of the myeloid proinflammatory marker sTREM2 in CSF of patients who receive ICI therapy compared to control. In a preclinical ICANS model, microglia assumed an ameboid active conformation, expressed higher level of the activation marker CD80 and TREM2 and showed higher level of TNF alpha and of the TNF upstream kinase p38-MAPK. Also in this model, microglia depletion and not T cell depletion reverted the neurocognitive deficits induced by CAT T cell treatment. As potential therapeutic approach, CAR T cell receiving mice treated with the inhibition of TAK1/TNF signaling takinib showed less neurocognitive than controls. Taken together, these results describe for the first time the role of microglial activation in neurological side effects of checkpoint-inhibitor and CAR T cell therapy and, if confirmed show a potential specific treatment for microglia activation in ICANS. Acute graft versus host disease involving the gastrointestinal tract (GI GVHD) is associated with the highest non-relapse mortality after allogeneic hematopoietic cell transplantation and represents the major risk factor for steroid resistance. A recent clinical trial showed superiority of ruxolitinib over other second-line therapies in steroid-refractory GVHD and specific approaches aiming gastrointestinal regeneration in GVHD are recently studied in preclinical models. Real world data on ruxolitinib specifically on GI GVHD are lacking. In a retrospective single-center cohort study on 144 patients developing GI GVHD in a 6-year period, steroid refractory patients experienced a poor outcome (35% 5y-overall survival) and a low rate of complete response to ruxolitinib (13%). Patients who achieve response, though, has an improved outcome

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Universität Freiburg, Dissertation, 2024

Classification and Topics

• Keyword: Immuntherapie ; Krebs ; Tiermodell ; Mikroglia

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2024
• Creator: Biavasco, Francesca
• Contributor: Zeiser, Robert ; Hasselblatt, Peter ; Albert-Ludwigs-Universität Freiburg. Medizinische Fakultät ; Universitätsklinikum Freiburg. Klinik für Innere Medizin I

Further information

• DOI: 10.6094/UNIFR/258689
• URN: urn:nbn:de:bsz:25-freidok-2586897
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 15.08.2025, 7:35 AM CEST