Blocking MAPK Activation and Immune Checkpoints Reverse Immune Dysfunction and Reduce Disease in a Mouse Model of LCH

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207⁺ dendritic cells (DCs) with persistent mitogen-activated protein kinase (MAPK) pathway activation. Standard of care chemotherapy strategies are inadequate or overly toxic for the majority of patients with multisystem disease. The mechanisms underlying development of inflammation in LCH lesions are poorly understood, and potential for immunotherapy has not been determined. Analysis of the LCH lesion identified the most prominent immune cells as T lymphocytes, second only to pathologic CD207⁺/CD1a⁺ DCs (LCH DC). Both CD8⁺ and CD4⁺ T cells exhibited 'exhausted' phenotypes with high expression of the immune checkpoint inhibitor receptors. LCH DC cells also showed robust expression of ligands to checkpoint inhibitor receptors. Lesion CD8⁺ T cells exhibited blunted expression of Th1 cytokines with impaired effector function. In contrast, regulatory T cells (Tregs) isolated from LCH lesions demonstrated intact suppressive activity. Treatment of BRAFV600E^CD11c LCH mice with anti-PD-1, anti-TIM-3 and MEKi decreased the lesion size: MEKi treatment resulted in reduction of the myeloid compartment; anti-PD-1 and anti-TIM-3 were associated with reduction in the lymphoid compartment. However, combined treatment with MEKi and either anti-PD-1 or anti-TIM-3 significantly decreased both CD8+ T cell and myeloid LCH cells in a synergistic fashion. These results thus indicate MAPK hyperactivation in myeloid LCH cells drives recruitment and activation of functionally exhausted T cells within the LCH microenvironment. While the results from this study did not demonstrate a significant impact of checkpoint inhibition alone on tumor burden in experimental mice, combined MAPK and checkpoint inhibition may be a potentially effective therapeutic strategy for patients with LCH.