Oberle Lab

Tumor immunosuppression and lipid metabolism

Epidemiological data demonstrate that patients suffering from obesity and the metabolic syndrome have a higher risk to develop cancer. Obesity-associated metabolic perturbations foster tumor growth and progression by suppressing anti-tumor T cell activity and promoting a highly tumor-permissive microenvironment. Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of pathologically activated neutrophils and monocytes with immunosuppressive character that are predominantly present in patients suffering from cancer. Soluble, tumor-secreted cytokines such as M-CSF, GM-CSF, VEGF and IL-6, amongst others, stimulate aberrant myelopoiesis in the bone marrow, thereby leading to the expansion of MDSC and their recruitment into the tumor microenvironment. Once residing in the tumor, MDSC efficiently suppress anti-tumor T cell responses via amino acid depletion, reactive oxygen species production and the secretion of immunomodulatory cytokines, amongst others. Interestingly, previous research identified MDSC and tumor-associated macrophages as major drivers of obesity-associated immunosuppression in preclinical tumor models.

By using syngeneic murine tumor models, biochemical and functional cell biological methods as well as immunological assays, we try to understand how obesity-associated alterations in systemic lipid and glucose metabolism affect the immunosuppressive behavior of myeloid cells in the TME. Specifically, we aim at the identification of novel mechanisms that drive the activation and maturation of MDSC in the TME, thereby acquiring an immunosuppressive phenotype resulting in efficient inhibition of the anti-tumor T cell response.

^{Obesity and the Metabolic Syndrome affect various aspects of tumor immunosuppression. Specifically, we are interested in A) identifying lipid associated metabolic pathways that foster the immunosuppressive action of MDSC; B) detecting potential novel, obesity-associated activating ligands in the TME that engage MDSC-specific cell surface receptors; and C) unraveling MDSC-centered mechanisms that hinder the therapeutic efficacy of anti-angiogenic – and immunotherapy. Figure created in  https://BioRender.com}

Lipid mediators and immunosuppression. Obesity is associated with increased tumor burden and an immunosuppressive microenvironment. We use tumor models in mice with obesity and aim to uncover novel, MDSC-centered mechanisms that suppress the anti-tumor immune response. Thereby, we focus on obesity-associated metabolic changes that promote MDSC suppressive activity.

Ligands of MDSC in the TME. Once homing into the TME, MDSC are activated and suppress anti-tumor T cell activity. We apply a biotin-ligase-based proximity labeling approach to identifiy novel, scavenger receptor-specific ligands that are involved in MDSC activation.

MDSC in therapy resistance. Immune checkpoint blockade (ICB) and anti-angiogenic therapies (AAT) are common approaches to tackle malignant disease. Although many patients profit from these therapy regimens, acquired resistance mechanisms limit therapeutic efficacy. Uncovering MDSC-mediated resistance mechanisms is the focus of a translational research project in the lab.