Role and Mechanisms Exploration of Histamine and Its Receptors in the Progression of Peripheral T-Cell Lymphoma

Introduction: Peripheral T-cell lymphoma (PTCL) is a group of malignant lymphomas originating from mature T cells, characterized by clinical aggressiveness, rapid progression, and dismal survival outcomes. Elevated levels of inflammatory reactants are closely associated with poor prognosis. The incidence of PTCL in China is much higher than that in European and American countries, while basic and clinical research is relatively lagging behind. Hence, there is an urgent need for a comprehensive and systematic analysis of the tumor microenvironment of PTCL and discover new effective targets as well as reliable prognostic indicators. Objectives: This study intends to progressively analyze the spatial characteristics of PTCL tumors and the inflammatory microenvironment at the genomic, cellular, and animal levels, using single-cell RNA sequencing combined with image mass cytometry and other multi-omics methods. On this basis, it focuses on the role and molecular mechanism of the Histamine-HRH2 axis in PTCL disease progression and drug resistance, verifying it at the cellular and animal levels. The project aims to fully explore potential therapeutic targets, providing new ideas for optimizing treatment schemes and overcoming drug resistance in PTCL patients. Methods: By conducting single-cell RNA sequencing (scRNA-seq) and imaging mass cytometry (IMC), we conducted a comprehensive investigation of the complexity of inflammatory microenvironmen in PTCL. We unveiled the role and molecular mechanism of the Histamine-HRH2 axis in the progression of PTCL as well as the potential drug resistance regulatory mechanisms. Immunohistochemistry, immunofluorescence, and publicly available microarray datasets were used to validate these findings. Results: The present study highlighted histamine, an inflammatory mediator, was abundant in the microenvironment of PTCL and was associated with poor prognosis of patients. Histamine, upon interaction with the HRH2 receptor on tumor cell surfaces, triggers the secretion of CSF1, consequently inducing M2 macrophage polarization and mediates immune suppression. The expression of p-CREB and CEBPB were upregulated after the treatment of histamine, which mediated the transcriptional activation of CSF1. In addition, we uncovered that histamine and CSF1 played important roles in remodeling the tumor microenvironment of PTCL, and combination therapy with antihistamines and CSF1R inhibitors may effectively enhance tumor cell killing effect of HDAC inhibitor. Conclusions: In this study, we constructed comprehensive single-cell atlas of PTCL tumors and inflammatory microenvironment, using single-cell RNA sequencing combined with image mass spectrometry. On this basis, for the first time, we elucidated the role and molecular mechanism of histamine/HRH2 receptor axis in the progression of PTCL, explored potential therapeutic targets to provide new strategies for optimizing clinical treatment of PTCL patients.