The immune system collectively functions to recognize and protect tissues from infections, damage or malignant transformation. Appropriate innate and adaptive immune system interactions lead to highly efficient recognition and clearance of pathogens or transformed cells. Maladaptive interactions between these two systems however can result in harmful immunologic responses including chronic infections and development of cancer. Understanding the mechanisms behind these maladaptations, which share specific features with ineffective immunity in chronic infections, is crucial for achieving therapeutic benefits. Our goal here is to deploy a wide array of interdisciplinary approaches in order to perform a systematic, comparative, multi-layered and integrative analysis of the mechanisms responsible for inefficient immune responses, which are expected to provide novel therapeutic avenues for the restoration of efficient immunity in both, tumors and chronic infection.
Starting in 2018, we investigated how inappropriate function of the innate immune system affects adaptive immunity and contributes to inefficient anti-cancer immunity and chronification of infections. A special focus was placed on the role of tumor cell-derived factors, small molecule-based modulation of signaling pathways and the contribution of surface molecules or soluble mediators, like cytokines and coagulations proteases. Key findings of the first funding period describe the important contribution of tissue acidification, secreted factors and receptors of the coagulation system, metabolic reprogramming of cells and even far-fetching effects like microbiome-induced tonic type-1 interferon levels on the control of pathogen- and tumor-specific immune responses.
We are now planning to further understand in detail how soluble mediators contribute to immune dysfunction and how this can be regulated to gain therapeutic benefits. We also want to achieve a better understanding of the role of the microbiome and microbial metabolites as well as tissue acidification as a consequence of enhanced aerobic glycolysis. Our observations from the initial funding period suggest that the aforementioned factors crucially contribute or interfere with systemic adaptive immune responses. To better appreciate the cellular crosstalk in tumor-, persistently infected and healthy tissue, we will develop new methods, which genuinely reflect the heterogeneity of tumors and infected tissues and allow a spatial resolution of different cell populations from both, mouse and human tissues.
All of this will lead to an unprecedented comparative analysis of the various immune evasion mechanisms in cancers and in chronic infections. This will result in a detailed map of common and disease-specific immune escape checkpoints and provide the basis for future stratified therapies allowing the development of precision medicine to treat chronic infections and cancer.