The immune cell landscape of glioblastoma patients highlights a myeloid-enriched and immune suppressed microenvironment compared to metastatic brain tumors

Abstract

IntroductionBrain metastases (BrM), which commonly arise in patients with melanoma, breast cancer and lung cancer, are associated with a poor clinical prognosis. In this context, the tumor microenvironment (TME) plays an important role since it either promotes or inhibits tumor progression. Our previous studies have characterized the immunosuppressive microenvironment of glioblastoma (GBM). The aim of this study is to compare the immune profiles of BrM and GBM in order to identify potential differences that may be exploited in their differential treatment.MethodsTumor and/or blood samples were taken from 20 BrM patients and 19 GBM patients. Multi-parametric flow cytometry was used to evaluate myeloid and lymphoid cells, as well as the expression of immune checkpoints in the TME and blood. In selected cases, the immunosuppressive ability of sorted myeloid cells was tested, and the ex vivo proliferation of myeloid, lymphoid and tumor cell populations was analyzed.ResultsHigh frequencies of myeloid cells dominated both the BrM and GBM landscapes, but a higher presence of tumor-associated macrophages was observed in GBM, while BrM were characterized by a significant presence of tumor-infiltrating lymphocytes. Exhaustion markers were highly expressed in all T cells from both primary and metastatic brain tumors. Ex vivo analysis of the cell cycle of a single sample of a BrM and of a GBM revealed subsets of proliferating tumor cells and blood-derived macrophages, but quiescent resident microglial cells and few proliferating lymphocytes. Macrophages sorted from a single lung BrM exhibited a strong immunosuppressive activity, as previously shown for primary GBM. Finally, a significant expansion of some myeloid cell subsets was observed in the blood of both GBM and BrM patients.DiscussionOur results define the main characteristics of the immune profile of BrM and GBM, which are distinguished by different levels of immunosuppressive myeloid cells and lymphocytes devoid of effector function. Understanding the role of the different cells in establishing the metastatic setting is critical for improving the therapeutic efficacy of new targeted immunotherapy strategies.

The Immunomodulatory Effects of Fluorescein-Mediated Sonodynamic Treatment Lead to Systemic and Intratumoral Depletion of Myeloid-Derived Suppressor Cells in a Preclinical Malignant Glioma Model

“…Increased intratumoral and systemic MDSC levels are correlated with decreased survival and inevitably with a failure of the antitumor immune response [30]. The impact observed on peripheral immune cells after FL administration can be explained by the ability of leukocytes to take up and accumulate FL, as very recently described by Musca and coworkers [3]. The data from these studies and our study need to be further investigated to clarify the immunostimulatory potential of FL, either alone or in combination with SDT.…”

“…Glioblastomas are still the most urgent unmet needs in oncology. The immune landscape of glioblastoma is characterized by a myeloid-enriched and immunosuppressive microenvironment, which is demonstrated by their resistance to therapies, including immunotherapy [1][2][3][4][5][6].…”

IRF8-driven reprogramming of the immune microenvironment enhances anti-tumor adaptive immunity and reduces immunosuppression in murine glioblastoma

“…The SB28 model of GBM is clinically relevant, with its low mutational burden and resistance to immune checkpoint blockade therapy 27 . Like human GBM, SB28 orthotopic tumors are highly infiltrated by myeloid cells, which comprise the vast majority of intra-tumoral immune cells 28,29 (Fig. 1a).…”