Inhaled CpG increases survival and synergizes with checkpoint inhibition in lymphangioleiomyomatosis

Rationale: Lymphangioleiomyomatosis (LAM) is a devastating disease primarily found in women of reproductive age that leads to cancer-like cystic destruction of the lungs. Recent work has shown that LAM causes immunosuppression and that checkpoint inhibitors can be used as LAM treatment. IN lung canc...

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Bibliographic Details
Published in:bioRxiv 2023-02
Main Authors: Amosu, Mayowa, Mccright, Jacob C, Bennett, Yang, Juan Grano De Oro Fernandez, Moore, Kaitlyn, Gadde, Havish S, Kaluzienski, Michele, Maisel, Katharina
Format: Article
Language:English
Subjects:
Agonists
Animal models
CD4 antigen
Flow cytometry
Immune checkpoint inhibitors
Immunosuppression
Immunotherapy
Inflammation
Lung cancer
Lungs
Lymphocytes T
Metastases
PD-1 protein
Phenotypes
TLR9 protein
Toll-like receptors
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Summary:Rationale: Lymphangioleiomyomatosis (LAM) is a devastating disease primarily found in women of reproductive age that leads to cancer-like cystic destruction of the lungs. Recent work has shown that LAM causes immunosuppression and that checkpoint inhibitors can be used as LAM treatment. IN lung cancer, TLR agonist, in particular TLR9 agonist CpG has been shown to be effective. Objectives: Here we investigate the use of TLR9 agonist CpG as LAM immunotherapy in combination with checkpoint inhibitor, anti-PD1 and assess induced changes in anti-LAM immunity. Methods: We used a murine model of metastatic LAM to determine survival after intranasal treatment with TLR9 agonist CpG at two doses and in combination the checkpoint inhibitor immunotherapy, anti-PD-1. We used histology and flow cytometry to assess overall inflammation as well as changes in the immune response upon treatment. Measurements and Main Results: We found that local administration of CpG enhances survival in a murine model of LAM and that a lower dose more effectively balanced the inflammation induced by CpG with the anti-LAM therapeutic benefits. We also found that CpG reduces regulatory T cell infiltration in LAM lungs and that CD4 helper T cells are skewed toward pro-inflammatory phenotypes. We also found that CpG treatment is effective in both early stage and progressive disease and that CpG is synergistic with previously tested anti-PD1 therapy. Conclusions: We have found that TLR9 agonist CpG can be used as LAM immunotherapy and effectively synergizes with anti-PD1 therapy in LAM.Competing Interest StatementThe authors have declared no competing interest.
DOI:10.1101/2023.02.06.527331