Intranasal adjuvant immunotherapy re-activates immunity and enhances survival in murine metastatic Lymphangioleiomyomatosis

Abstract

Abstract Lymphangioleiomyomatosis (LAM) is cystic lung disease affecting primarily women of age. Currently there is no cure for this disease and only modest progress has been made with the introduction of sirolimus as LAM treatment. Recently, we and others have identified that LAM may also induce immunosuppression, similar to cancer. Adjuvant-based therapies like toll-like receptor (TLR) agonists are a promising strategy to activate cancer immunity. We used a murine model of metastatic LAM, to test therapeutic efficacy of TLR agonists PolyI:C, MPLA, and CpG, administered intranasally 2x/week. We found that only CpG enhances survival in murine LAM and that this treatment synergized with anti-PD1 therapy, which we had previously found to enhance survival in murine LAM. We found that the inflammation induced by CpG must be carefully balanced with its beneficial effects – in early disease, 5 μg of CpG was more beneficial than 10 μg. However, in progressive disease, 10 μg did not enhance survival while 20 μg CpG did. Furthermore, we found that a single dose of CpG reduced regulatory T cells and migratory dendritic cells (mDCs) and increased ICOS on T cells in the lungs. CpG also increased mDCs in the lymph nodes, and these were reduced after CCR7 blockade. We also found that repeated administration of CpG reduced immune cell infiltration into the lungs, which suggests a tolerogenic effect that may contribute to the incomplete survival. Overall, our data suggest that CpG may be a new treatment for LAM, that its beneficial effects may be in part mediated by CCR7 dependent DC migration, and that dose and inflammation must be carefully monitored to optimize therapeutic efficacy. Supported by the ALA Dalsemer Award and LAM Foundation Career Development Award.