Immunological and Translational Aspects of Glycolytic Metabolism inVarious Human Tumor Entities

摘要

Background: Previous experimental and clinical studies have shown that lactate concentra-tions of 10 mM and more in solid malignant tumors may inactivate cytotoxic T cells as a major compo-nent of the immune defense of the tumor host. Additionally, it has been demonstrated recently that glu-cose depletion within cancerous tissue to concentrations of 1 mM and less may inhibit the T cell-mediated immune response, as well. To evaluate the significance of lactate accumulation compared toglucose depletion in cancers, we have revisited previous data using the technique of induced metabolicBioluminescence Imaging (imBI) in various entities of human tumor xenografts and tumors in the clin-ic. These tumor entities comprise squamous cell carcinomas of the cervix and of the head and neck,ovarian cancer metastases, rectal adenocarcinomas, glioblastomas, and melanomas. Tissue lactate levelsin metastatic primary tumors were 1.5- to 2-times higher than those in non-metastatic primaries, and thiswas true for both patient cancers and corresponding tumor xenografts. Immunologically relevant lactateaccumulation (>= 10 mM) occurred in a large majority of all tumors investigated. In contrast, tumorswith average glucose concentrations of 1 mM and less were rarely found in general with the striking ex-ception of rectal adenocarcinomas, where 67 % of all tumors were low glucose malignancies. Conclusion: lactate accumulation in malignant tissue may be quantitatively more relevant for the im-mune escape compared to glucose depletion. However, in rectal adenocarcinomas both high lactate andlow glucose concentrations may substantially contribute to the inhibition of the immune defense.