The role of GM-CSF in the modulation of anti-tumor immunity in myeloproliferative neoplasms.

• Applicant: Dr. Tobias Wertheimer
• Subject Area: Hematology, Oncology ; Immunology
• Term: from 2021 to 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 463384799

• Final Report Year: 2024

Final Report Abstract

The initial proposal aimed to elucidate the contribution of the cytokine GM-CSF as a communication signal between T cells and myeloid cells in the tumor microenvironment of myeloproliferative diseases. Albeit preliminary data suggest no major influence on GM-CSF on the disease progression of MPN in a preclinical model, the research question could so far not be sufficiently and conclusively answered most importantly due to organizational delays. Therefore, I investigated the role of Interleukin-23 (IL-23), which is another proinflammatory cytokine governing crosstalk between myeloid cells and T cells. Surprisingly, it was found that IL- 23 in the context of the tumor microenvironment (TME) is sensed by a subset of tumorinfiltrating regulatory T cells (Treg cells) marked by the expression of the IL-23 receptor (IL23R) in the murine und human TME. This Treg cell population displayed a highly activated and suppressive phenotype. The use of multiple preclinical cancer models in combination with ablation of Il23r in Tregs revealed that they are responsible for the tumor-promoting effect of IL-23. Mechanistically, our data demonstrate that IL-23 sensing by Treg cells represents a crucial signal driving the maintenance and stabilization of effector Treg cells involving the transcription factor Foxp3. This not only shows an unexpected immunosuppressive property of an otherwise pro-inflammatory cytokine, but also identifies the IL-23/IL-23R axis as a novel means of eliciting anti-tumor immunity.

Publications

• IL-23 stabilizes an effector Treg cell program in the tumor microenvironment. Nature Immunology, 25(3), 512-524.
  Wertheimer, Tobias; Zwicky, Pascale; Rindlisbacher, Lukas; Sparano, Colin; Vermeer, Marijne; de Melo, Bruno Marcel Silva; Haftmann, Claudia; Rückert, Tamina; Sethi, Aakriti; Schärli, Stefanie; Huber, Anna; Ingelfinger, Florian; Xu, Caroline; Kim, Daehong; Häne, Philipp; Fonseca, da Silva, André; Muschaweckh, Andreas; Nunez, Nicolas; Krishnarajah, Sinduya ... & Becher, Burkhard