Modifying macrophage polarization to improve cancer immunotherapies

• Applicants: Dr. Astrid Alflen; Dr. Toszka Bohn
• Subject Area: Hematology, Oncology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 518821558

Cancer immunotherapies have revolutionized the field of hematology and oncology and resulted in impressive treatment responses for relapsed or refractory advanced stage cancer patients. However, so far the majority of patients doesn’t benefit from these new treatment options, highlighting the need for improvements in this field. The most famous representatives for treatment possibilities in immuno-oncology are T cell-based immunotherapies like immune checkpoint blockade, adoptive cell therapy (ACT) and cancer vaccines. Efficacy of these T cell-based immunotherapies is limited by multiple factors of the tumor microenvironment that can impact on cytotoxic T cell functionality. The immunosuppressive tumor microenvironment consists of metabolic factors like low pH, comprises natural killer cells that can serve as a cytokine sink in ACT, direct immunosuppressive cells like regulatory T cells, myeloid-derived suppressor cells and myeloid cells including macrophages polarized towards an anti-inflammatory phenotype. Here, tumor-associated macrophages (TAM) turned out to be one of the major contributors leading to impaired tumor control by the immune system within the tumor microenvironment. One reason for the growing interest in TAM is their enormous abundance in the tumor microenvironment of most solid malignancies and a strong correlation between the density of macrophages and poor survival in different cancer entities. Our work hypothesis is that anti-tumor immune responses are limited by anti-inflammatory macrophages. Therefore, the central goal of this project is to better understand TAM in immunotherapy-treated patients and to identify molecules and signaling pathways promoting an anti-inflammatory macrophage phenotype. First, we will characterize macrophages in melanoma tumor samples and study the correlation with treatment response to immunotherapies. By identifying characteristics of peripheral blood monocytes in patients with high TAM infiltration in melanoma lesions we additionally aim to find liquid biomarkers. To identify molecular targets in macrophages promoting a pro-inflammatory polarization in an unbiased way, we will further perform a CRISPR knockout screen in macrophages in vitro. Subsequently, screen findings will be validated in vitro and in vivo and identified targets will be studied for the underlying mechanism. In parallel, to generally improve translatable studies in this field, patient-derived experimental systems will be established for functional in vitro studies, for which we plan to use autologous tumor cells, tumor infiltrating lymphocytes and macrophages in functional assays. Taken together, with this project we aim to better understand TAM in the context of cancer immunotherapies and identify new potential targets to improve the outcome of cancer patients.

• DFG Programme: Research Grants