''The Immune-regulatory Role of the Transcription factor PU.1 in Lung cancer.''

• Applicant: Professorin Dr. Susetta Finotto, Ph.D.
• Subject Area: Pneumology, Thoracic Surgery ; Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 541068953

Immunotherapy with PD-1/PD-L1 checkpoint inhibitors appears to be a promising approach for activation of anti-tumor immune responses of the host in the pathogenesis of cancer. However, due to low patient response rates (20 %), this immunotherapy for lung cancer (NSCLC) still needs to be improved. To this aim, understanding the role of cytokines in the context of tumor infiltrating lymphocytes (TIL) and immune escape mechanisms appeared to be a promising strategy for discovering new supportive treatment options. In line with that, we previously described a key role of the transcription factor T-bet in NSCLC tumor rejection, which is the direct transcription factor of the anti-tumoral cytokine IFNγ. Additionally, we recently identified IL-9 supporting conditions in the tumor microenvironment with simultaneously favouring the development of regulatory T cells. As we started to shed light into the transcriptional regulation of IL-9 expression and its role in anti-tumor immunity, we recognized the IL-9 co-transcription factor PU.1. With preliminary data we could make up a role of PU.1, which is encoded by the SPI1 gene in humans, in the context of NSCLC through presence in Natural Killer (NK) cells. PU.1 is further involved in controlling the expansion of progenitor NK cells as well as the homeostasis and differentiation of mature NK cells. Preliminary findings suggest a pro-tumoral role of PU.1 in NK cells. In the local lymph nodes of these patients, we also identified presence of PU.1 that needs further cellular characterization. This led us to a hypothesis, that a targeted downregulation of PU.1 in NK cells would restore NK cell homeostasis and would contribute to a beneficial effect in NSCLC. Therefore, with this grant we want to focus on a detailed understanding of the role of PU.1 in NK cell in non-small cell lung cancer.

• DFG Programme: Research Grants