Overcoming T-cell exhaustion in LCH: PD-1 blockade and targeted MAPK inhibition are synergistic in a mouse model of LCH

Abstract

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 is inadequate for most patients with multisystem disease, and optimal strategies for relapsed and refractory disease are not defined. The mechanisms underlying development of inflammation in LCH lesions, the role of inflammation in pathogenesis and potential for immunotherapy are unknown. Analysis of the immune infiltrate in LCH lesions identified the most prominent immune cells as T lymphocytes. Both CD8+ and CD4+ T cells exhibited 'exhausted' phenotypes with high expression of the immune checkpoint receptors. LCH DCs showed robust expression of ligands to checkpoint receptors. Intra-lesional CD8+ T cells showed blunted expression of Tc1/Tc2 cytokines and impaired effector function. In contrast, intra-lesional regulatory T cells (Tregs) demonstrated intact suppressive activity. Treatment of BRAFV600ECD11c LCH mice with anti-PD-1 or MAPK inhibitor reduced lesion size, but with distinct responses: whereas MAPK inhibitor treatment resulted in reduction of the myeloid compartment, anti-PD-1 treatment was associated with reduction in the lymphoid compartment. Notably, combined treatment with MAPK inhibitor and anti-PD-1 significantly decreased both CD8+ T cell and myeloid LCH cells in a synergistic fashion. These results are consistent with a model that MAPK hyperactivation in myeloid LCH cells drives recruitment of functionally exhausted T cells within the LCH microenvironment and highlight combined MAPK and checkpoint inhibition as a potential therapeutic strategy.

Improving CAR T-Cell Persistence

“…During the interaction between T-cells and tumor cells, integrated signals coming both from cell-to-cell contacts and from cytokine-dependent crosstalk regulate T-cell expansion, differentiation, and persistence [ 29 , 30 , 111 ]. Two main pathways involved in this transduction network are the mitogen-activated protein kinase (MAPK) and PI3K/AKT/mTOR pathways [ 112 , 113 , 114 ]. MAPKs, a family of serine/threonine kinases, regulate a variety of cellular responses to stimuli including proliferation, migration, and differentiation.…”

BRAF V600E Mutation in Cell-Free DNA, Rather than in Lesion Tissues, at Diagnosis Is An Independent Prognostic Factor in Children with Langerhans Cell Histiocytosis

“…Two mouse models of LCH were established recently. In these LCH models, MAPK inhibitors were capable of restoring migration and apoptosis potential, decreasing disease burden, and reducing the histiocytic infiltration of alveoli and peribronchiolar stroma in the lungs, sinusoidal distension and periportal cellular infiltration in the liver [28,29]. New models with or without cfBRAF V600E could be established based on the above mouse models to test the clinical value of cfBRAF V600E and the efficacy of MAPK inhibitors in cfBRAF V600E -positive mice.…”

PTP4A3 Is a Prognostic Biomarker Correlated With Immune Infiltrates in Papillary Renal Cell Carcinoma

“…This study is the first reported association of PTP4A3 and PD1 in renal cancer. The combination of PTP4A3 with immune cells is proposed as a predictor for immunotherapy response and prognosis in renal cancers, with potential applications in other cancer types such as NSCLC or gastric cancer as well ( 57 , 58 ). These findings further confirm the relationship of PTP4A3 expression to immune infiltration in KIRP, suggesting that PTP4A3 influences immune escape in the renal cancer microenvironment.…”