Rewired Metabolism Regulates Vessel Normalization and Immunosuppression

项目总结

Project Summary Multiple hallmarks distinguish tumors from their normal counterparts. Among these are escape of immune-surveillance and aberrant metabolism (increased glycolysis). Each of these hallmarks has been extensively investigated. Significant progress has been made, especially with the recent emergence of anti- immune checkpoint therapies. However, these therapies still benefit a subset of patients, with efficacy seen only in few cancer types. This reflects the heterogeneity seen between tumors that constantly evolve resistance mechanisms to promote tumor progression. In collaboration with Dr. Sreekumar our long-term goal is to overcome treatment resistance and metastasis in breast and other cancers by integrating our expertise in the areas of tumor immunology and metabolism. In this context, our metabolomics data coupled with follow up studies have highlighted the importance of tryptophan metabolism especially the kynurenine axis in regulating tumor immune interactions. Among the kynureine pathway enzymes, we identified Kynurenine Amino Transferase (AADAT) to be elevated in aggressive basal like tumors and significantly associated with poor clinical outcome in patients and negatively associated with patient’s response to immune therapy in melanoma. AADAT converts KYN to kynurenic acid, in the process using α ketoglutarate, a key component of TCA) as the co-substrate. Our preliminary data demonstrates that AADAT single-handedly regulates energy metabolism in the tumors and immune cell infiltration in the microenvironment potentially mediated via HIF 1α and its consequent effect on vessel normalization (VN), a homeostatic process involving improved pericyte attachment to endothelium, increased blood perfusion, de-creased vessel permeability, and consequently reduced hypoxia. We had earlier demonstrated a novel mutually regulatory loop between VN and immune stimulation in tumor microenvironment that drove the tumor either into a hot” state with self-reinforcing VN and immune cell infiltration or into a “cold” state “stuck” with poorly-developed vessels and minimally infiltrated immune cells and resistant to therapies. Moreover, AADAT depletion also led to activation of IFNγ signaling in cancer cells, further activating anti-tumor immunity. Based on all of the above, we hypothesize that AADAT promotes cancer progression and therapeutic resistance by stimulating immune suppression and energy metabolism by regulating HIF α expression and activity. Our specific aims are: Aim 1: To determine the mechanisms underpinning AADAT’s immunosuppressive functions in various immunocompetent breast cancer and melanoma models. Aim 2: Determine mechanism of action of AADAT by modulating intra-tumoral HIF1α signaling axis. Aim 3 Determine if genetic depletion or pharmacological inhibition of AADAT sensitizes breast cancer and melanoma to immune checkpoint blockade therapies (ICBT). The impact of our study is to mark AADAT as a distinct regulator of immune and metabolism axes, in the tumor and surrounding microenvironment which if proven will reveal a single therapeutically actionable target for aggressive cancers.