The immune suppressive microenvironment of human gliomas depends on the accumulation of bone marrow-derived macrophages in the center of the lesion

Journal for ImmunoTherapy of Cancer

Hideho Okada¹  Aaron Diaz¹  Marina Vettore²  Sara Magri²  Marta D’Andolfi²  Samantha Solito²  Jean-Pierre Benoit³  Giovanna Lollo⁴  Alessandro Della Puppa⁵  Laura Pinton⁶  Paola Del Bianco⁶  Elena Masetto⁶  Susanna Mandruzzato⁶ 

[1] Department of Neurological Surgery, University of California;Department of Surgery, Oncology and Gastroenterology, University of Padova;INSERM U1066/CNRS 6021 University of ANGERS;LUNAM Universite - Micro et Nanomedecines Biomimetiques;Neurosurgery Unit, Azienda Ospedaliera di Padova;Veneto Institute of Oncology IOV – IRCCS;

关键词: Innate immunity;    Tumor microenvironment;    Tumor immunology;    Immunological tolerance;    Brain cancer;   

DOI  :  10.1186/s40425-019-0536-x

来源: DOAJ

【 摘 要 】

Abstract Background Systemic and local immune suppression plays a significant role in glioma progression. Glioma microenvironment contains both brain-resident microglial cells (MG) and bone marrow-derived macrophages (BMDM), but the study of their functional and immune regulatory activity has been hampered until now by the lack of markers allowing a proper identification and isolation to collect pure populations. Methods Myeloid and lymphoid infiltrate were characterized in grade II, III and IV gliomas by multicolor flow cytometry, along with the composition of the cell subsets of circulating myeloid cells. Macrophages were sorted and tested for their immunosuppressive ability. Moreover, following preoperative administration of 5-aminolevulinic acid to patients, distinct areas of tumor lesion were surgically removed and analyzed, based on protoporphyrin IX fluorescence emission. Results The immune microenvironment of grade II to grade IV gliomas contains a large proportion of myeloid cells and a small proportion of lymphocytes expressing markers of dysfunctional activity. BMDM and resident MG cells were characterized through a combination of markers, thus permitting their geographical identification in the lesions, their sorting and subsequent analysis of the functional characteristics. The infiltration by BMDM reached the highest percentages in grade IV gliomas, and it increased from the periphery to the center of the lesion, where it exerted a strong immunosuppression that was, instead, absent in the marginal area. By contrast, MG showed little or no suppression. Functional differences, such as iron metabolism and phagocytosis, characterized resident versus blood-derived macrophages. Significant alterations in circulating monocytes were present in grade IV patients, correlating with accumulation of tumor macrophages. Conclusions Grade IV gliomas have an alteration in both circulating and tumor-associated myeloid cells and, differently from grade II and III gliomas, show a significant presence of blood-derived, immune suppressive macrophages. BMDM and MG have different functional properties.

【 授权许可】

Unknown