Microbiome depletion reduces Immune Checkpoint Blockade (ICB) efficacy in a Murine Metastatic Osteosarcoma (mOS) model 4501

Abstract Description Modulation of the microbiome has been found to influence immune cell function, with recent evidence suggesting these changes can significantly alter immunotherapy outcomes for cancer patients. Broad-spectrum antibiotics (Abx), which significantly reduce microbiome diversity, have been shown to diminish CD3+ T cell presence in lungs of saline-treated mice during respiratory infections, compared to untreated controls; a result important to consider for immunotherapies targeted to respiratory organs. Additionally, Abx are commonly administered to patients undergoing immune checkpoint blockade (ICB) for cancer, who are at an increased risk of nosocomial infections. These results are relevant for immunotherapies for metastatic osteosarcoma (mOS), which frequently metastasizes to the lungs. We have previously shown ICB given to mice inoculated with an mOS cell line resulted in ∼50% survival and complete tumor clearance. Our current study demonstrates the role of long-term Abx treatment and subsequent microbiome depletion when administered in conjunction with ICB for mOS, showing a significant reduction in ICB efficacy for mOS and resulting in mortality outcomes comparable to control mice untreated with ICB. We also examine additional implications for T immune cell homing during mOS and Abx treatment, with analysis of changes in mucosal homing markers such as CCR9 and α4β7 integrin, and immune memory markers CCR7 and CD62L, essential for long-term tumor clearance of mOS. Funding Sources Funding for this project was provided by Jeff Gordon Children’s Foundation (JGCF). Funding support for preliminary data that lead to the work described here was provided by Sarcoma Foundation of America (SFA) Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)