Our group is studying interactions within the microenvironment of solid tumors that cause immune-suppression and tumor immune evasion. Our overall aim is to understand and break through limitations of current immunotherapies. We want to develop novel immunotherapy concepts by modulating and reprogramming specific immune cell compartments to achieve optimal immunity against tumors. Questions that fuel our research are: How can we empower antigen-presenting cells to prime effective tumor-directed T cell responses? What antigen-presenting cell phenotypes play a role in T cell polarization and restimulation at the tumor site and how do they drive/limit T cell exhaustion? What factors drive T cell exhaustion in the tumor microenvironment and the draining lymph node? What specific pathways need to be targeted in tumor-associated myeloid cells to break their immune-suppressive properties?
To achieve our goals, we combine cell-culture based high-throughput technologies with mechanistic in vivo studies, single-cell transcriptomics and immune-profiling of patient-derived tumor material.
The microenvironment of solid tumors is characterized by a multitude of immune-suppressive factors, such as cytokines, high apoptotic cell load, unique extracellular matrix composition, hypoxia, scarcity of nutrients, metabolic waste products, and others. As a result, the functionality of many different immune and stromal cell populations is compromised, and tumor immune evasion is facilitated. In addition to cancer cells, various immune cell subsets take part in shaping the suppressive tumor microenvironment, which in turn locally drives cancer-associated immune-regulatory phenotypes of monocytes, macrophages, fibroblasts and dendritic cells, often coupled with regulatory T cells and exhausted T cells that are unable to mount tumor-directed cytotoxic responses. In our group we aim to target immune-suppressive phenotypes of myeloid cells, paired with already established immunotherapies such as immune checkpoint blockade, to allow for optimal immune responses within the TME. Our ultimate goal is to identify cellular, molecular and spatial determinants that stimulate or suppress human tumor immunity and to target suppressive phenotypes, while enabling effector populations.
Antigen-specific tumor-directed immune responses
Tumor-directed T cell responses are a prerequisite for successful immunotherapy, however, often T cells have an exhausted phenotype in the tumor microenvironment and fail to eliminate tumor cells. Exhausted T cells are functionally defined by limited cytokine production and cytotoxic effector function and inefficiency to clear the cellular source of antigen. Unlike functional memory and effector T cells, exhausted T cells are dependent on persistence of presented antigen. Hence, direct antigen-presenting cell/T cell contact is critical in driving T cell exhaustion. We are exploring how polarization/restimulation with different tumor-associated antigen-presenting cells shape T cell phenotypes and how different antigen-presenting cell subsets and phenotypes drive or limit antigen-specific anti-tumor immunity.
Immune Checkpoint Blockade in solid tumors
The development of immunotherapies, particularly those blocking the immune checkpoint PD-1/PD-L1, has revolutionized lung cancer treatment. Paradoxically, the mechanisms of action of PD-1/PD-L1 blockade are still incompletely understood and only a subset of patients responds to immune checkpoint blockade (ICB). PD-L1 expression on both infiltrating immune cells and/or tumor cells can be predictive for therapeutic success of ICB, suggesting that multiple mechanisms for T cell suppression involving PD-L1 expression on different compartments exist. We are trying to understand what antigen presenting cell types are involved in mediating responses to ICB; whether the mechanisms of action require antigen presenting cell/T cell interactions in the draining lymph nodes or at the tumor site; and what stages of T cell differentiation/maturation are targeted.