Investigating the Effects of Indoleamine 2-3-Dioxygenase Pathway Blockers in Combination with Chemotherapy and Radiation Treatments on Complement Production in Dendritic Cells and Macrophages
Previous research has shown that immune responses are of critical importance in tumor clearance after chemotherapy and radiation treatments. We hypothesize that responsiveness of patients to these treatments is dependent on the responsiveness of the immune system – specifically, the indoleamine 2,3-dioxygenase (IDO) pathway. This pathway is a natural counter-regulatory mechanism that inhibits immune and inflammatory responses, and in the case of cancer, is capable of suppressing the desired immune response against the tumor. The Johnson Lab has shown that blocking IDO drives deposition of complement C3 within tumors and that complement C3 is mechanistically required for IDO-blockade to synergize with chemo-radiotherapy to prolong survival (Li, et al. 2014, JITC). Preliminary data (unpublished) indicated that the source of complement deposition during IDO-blockade is not circulating plasma complement, but instead active production by local myeloid-lineage cells in the tumor microenvironment.
This project will use well-established mouse tumor models to test the hypothesis that IDO protects tumors from the full effects of standard chemotherapy and radiation therapy by negative regulation of local complement production by myeloid-lineage cells in the tumor microenvironment. Mice will be treated with and without indoximod (an IDO blocker), and with standard chemotherapy plus targeted (stereotactic) irradiation. The tumor and the tumor-draining lymph nodes will be collected separately after treatment. Macrophages and dendritic cells will be separated from each tissue source using MACS beads and briefly cultured ex vivo, and culture supernatant will be analyzed by ELISA for quantitation of specific complement proteins (C3 and C5).