BackgroundCorticosteroids are routinely utilized to alleviate edema in patients with intracranial lesions and are first-line agents to combat immune-related adverse events (irAEs) that arise with immune checkpoint blockade treatment. However, it is not known if or when corticosteroids can be administered without abrogating the efforts of immunotherapy. The purpose of this study was to evaluate the impact of dexamethasone on lymphocyte activation and proliferation during checkpoint blockade to provide guidance for corticosteroid use while immunotherapy is being implemented as a cancer treatment.MethodsLymphocyte proliferation, differentiation, and cytokine production were evaluated during dexamethasone exposure. Human T cells were stimulated through CD3 ligation and co-stimulated either directly by CD28 ligation or by providing CD80, a shared ligand for CD28 and CTLA-4. CTLA-4 signaling was inhibited by antibody blockade using ipilimumab which has been approved for the treatment of several solid tumors. The in vivo effects of dexamethasone during checkpoint blockade were evaluated using the GL261 syngeneic mouse intracranial model, and immune populations were profiled by flow cytometry.ResultsDexamethasone upregulated CTLA-4 mRNA and protein in CD4 and CD8 T cells and blocked CD28-mediated cell cycle entry and differentiation. Naïve T cells were most sensitive, leading to a decrease of the development of more differentiated subsets. Resistance to dexamethasone was conferred by blocking CTLA-4 or providing strong CD28 co-stimulation prior to dexamethasone exposure. CTLA-4 blockade increased IFNγ expression, but not IL-2, in stimulated human peripheral blood T cells exposed to dexamethasone. Finally, we found that CTLA-4 blockade partially rescued T cell numbers in mice bearing intracranial gliomas. CTLA-4 blockade was associated with increased IFNγ-producing tumor-infiltrating T cells and extended survival of dexamethasone-treated mice.ConclusionsDexamethasone-mediated T cell suppression diminishes naïve T cell proliferation and differentiation by attenuating the CD28 co-stimulatory pathway. However, CTLA-4, but not PD-1 blockade can partially prevent some of the inhibitory effects of dexamethasone on the immune response.Electronic supplementary materialThe online version of this article (10.1186/s40425-018-0371-5) contains supplementary material, which is available to authorized users.

Glioblastoma is the most common and aggressive malignant primary brain tumor. Cellular heterogeneity is a characteristic feature of the disease and contributes to the difficulty in formulating effective therapies. Glioma stem-like cells (GSCs) have been identified as a subpopulation of tumor cells that are thought to be largely responsible for resistance to treatment. Intratumoral hypoxia contributes to maintenance of the GSCs by supporting the critical stem cell traits of multipotency, self-renewal, and tumorigenicity. This review highlights the interaction of GSCs with the hypoxic tumor microenvironment, exploring the mechanisms underlying the contribution of GSCs to tumor vessel dynamics, immune modulation, and metabolic alteration.

Cancers are composed of heterogeneous combinations of cells that exhibit distinct phenotypic characteristics and proliferative potentials. Because most cancers have a clonal origin, cancer stem cells (CSCs) must generate phenotypically diverse progenies including mature CSCs that can self-renew indefinitely and differentiated cancer cells that possess limited proliferative potential. However, no convincing evidence exists to suggest that only single CSCs are representative of patients' tumors. To investigate the CSCs' diversity, we established 4 subclones from a glioblastoma patient. These subclones were subsequently propagated and analyzed. The morphology, the self-renewal and proliferative capacities of the subclones differed. Fluorescence-activated cell sorting and cDNA-microarray analyses revealed that each subclone was composed of distinct populations of cells. Moreover, the sensitivities of the subclones to an inhibitor of epidermal growth factor receptor were dissimilar. In a mouse model featuring xenografts of the subclones, the progression and invasion of tumors and animal survival were also different. Here, we present clear evidence that a brain tumor contains heterogeneous subclones that exhibit dissimilar morphologies and self-renewal and proliferative capacities. Our results suggest that single cell-derived subclones from a patient can produce phenotypically heterogeneous self-renewing progenies in both in vitro and in vivo settings.