The immunosuppresssive role of interleukin 9 in lung cancer

• Applicant: Professorin Dr. Susetta Finotto, Ph.D.
• Subject Area: Hematology, Oncology ; Immunology ; Pneumology, Thoracic Surgery
• Term: from 2016 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 298128893

Lung cancer represents the leading cause of cancer deaths worldwide. Recent studies suggest that immunotherapy could be a promising approach to improve the prognosis for this disease. Tumour-infiltrating CD8+ T cells and T helper (Th)1-polarized CD4+ T cells are currently considered to be central players in the initiation and execution of anti-cancer immune responses driven by multiple immunotherapeutic agents. In the last grant period we identified that lung tumour cells induce immunosuppressive cytokines like TGFβ (Transforming growth factor β) that turn off anti-tumour immune-responses mediated by Th1 and cytotoxic T lymphocytes and promote immunosuppressive responses dominated by Tregs and T cells expressing IL-9, IL-10 and PD1. We discovered increased IL-9 production by Treg cells in NSCLC patients. Targeted deletion of IL-9 (IL-9-/-) in an experimental model of NSCLC resulted in successful lung tumour rejection in mice which was associated with induced CTL, reduced Foxp3+ Tregs and increased PD-1+CD4+ T cells. Treatment of lung tumour-bearing mice with anti-PD-1 antibodies did not significantly affect lung tumor growth demonstrating the need to optimize anti-PD-1 immunotherapy. Moreover, anti-PD-1 antibody treatment resulted in an induction of IL-9. For this reason, we next blocked IL-9 with anti-IL-9 antibodies in our murine lung carcinoma model, resulting in inhibition of tumor development. We finally detected IL-9R expression in lung tumour cells and in tumour-infiltrating lymphocytes (TIL). In conclusion, our findings led to the following new grant hypothesis (Fig 8): The lung tumour cells escape the immune response of the host by producing TGFβ to support immunosuppressive Tregs. Tregs use IL-4 together with TGFβ to produce IL-9. IL-9 supports tumour cell survival and induces the expression of PD-1 on T cells thereby inhibiting anti-tumour immune-responses. Moreover, anti-PD-1 antibody treatment induced IL-9 demonstrating the need to optimize anti-PD-1 immunotherapy. Therefore, we next want to improve current immunotherapies and apply a combination of anti-PD-1 and anti-IL-9 antibodies in our murine model of lung cancer. Furthermore, functional analysis will be performed upon anti-PD-1 and/or anti-IL-9 treatment in cultured lung cells and TILs isolated from patients with NSCLC. Analysis of anti-PD1/IL-9 antibodies ex vivo will help us to better set up pre-clinical conditions to improve immunotherapy against NSCLC. In additional studies, we will determine the mechanisms inducing IL-9 in NSCLC and will determine the functional effects of IL-9 on TIL and tumour cells in experimental NSCLC and cells from NSCLC patients. Finally, we will perform RNA seq analyses of CD4+ and CD8+ TIL in experimental NSCLC to uncover gene pathways controlled by IL-9. This project will therefore allow new insights into the functional role of IL-9 on TIL function and tumour growth in NSCLC and may open new avenues for immunotherapy in lung cancer.

• DFG Programme: Research Grants