In many aggressive cancers, such as glioblastoma multiforme (GBM), progression is enabled by local immunosuppression driven by the accumulation of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC). However, the mechanistic details of how Treg and MDSC are recruited in various tumors is not yet well understood. Here we report that macrophages and microglia within the glioma microenvironment produce CCL2, a chemokine that is critical for recruiting both CCR4+ Treg and CCR2+Ly-6C+ monocytic MDSC in this disease setting. In murine gliomas, we established novel roles for tumor-derived CCL20 and osteoprotegerin in inducing CCL2 production from macrophages and microglia. Tumors grown in CCL2 deficient mice failed to maximally accrue Treg and monocytic MDSC. In mixed-bone marrow chimera assays, we found that CCR4-deficient Treg and CCR2-deficient monocytic MDSC were defective in glioma accumulation. Further, administration of a small molecule antagonist of CCR4 improved median survival in the model. In clinical specimens of GBM, elevated levels of CCL2 expression correlated with reduced overall survival of patients. Lastly, we found that CD163-positive infiltrating macrophages were a major source of CCL2 in GBM patients. Collectively, our findings show how glioma cells influence the tumor microenvironment to recruit potent effectors of immunosuppression that drive progression.
Purpose Glioblastoma (GBM) is the most common form of malignant glioma in adults. Although protected by both the blood brain- and blood tumor-barriers, T cells actively infiltrate GBM. Previous work has shown that IDO, CTLA-4 and PD-L1 are dominant molecular participants in the suppression of GBM immunity. This includes IDO-mediated regulatory T cell (Treg; CD4+CD25+FoxP3+) accumulation, the interaction of T cell-expressed, CTLA-4, with dendritic cell-expressed, CD80, as well as the interaction of tumor- and/or macrophage-expressed, PD-L1, with T cell-expressed, PD-1. The individual inhibition of each pathway has been shown to increase survival in the context of experimental GBM. However, the impact of simultaneously targeting all three pathways in blood tumor-barriers, GBMs are actively infiltrated by T cells. Experimental Design and Results In this report, we demonstrate that, when dually-challenged, IDO-deficient tumors provide a selectively competitive survival advantage against IDO-competent tumors. Next, we provide novel observations regarding tryptophan catabolic enzyme expression, before showing that the therapeutic inhibition of IDO, CTLA-4 and PD-L1 in a mouse model of well-established glioma maximally decreases tumor-infiltrating Tregs, coincident with a significant increase in T cell-mediated long-term survival. In fact, 100% of mice bearing intracranial tumors were long-term survivors following triple combination therapy. The expression and/or frequency of T cell-expressed CD44, CTLA-4, PD-1 and IFN-γ depended on timing after immunotherapeutic administration. Conclusions Collectively, these data provide strong pre-clinical evidence that combinatorially-targeting immunosuppression in malignant glioma is a strategy that has high potential value for future clinical trials in patients with GBM.
Glioblastoma multiforme patients have a poor prognosis due to therapeutic resistance and tumor relapse. It has been suggested that gliomas are driven by a rare subset of tumor cells known as glioma stem cells (GSCs). This hypothesis states that only a few GSCs are able to divide, differentiate, and initiate a new tumor. It has also been shown that this subpopulation is more resistant to conventional therapies than its differentiated counterpart. In order to understand glioma recurrence post therapy, we investigated the behavior of GSCs after primary chemotherapy. We first show that exposure of patient-derived as well as established glioma cell lines to therapeutic doses of temozolomide (TMZ), the most commonly used antiglioma chemotherapy, consistently increases the GSC pool over time both in vitro and in vivo. Secondly, lineage-tracing analysis of the expanded GSC pool suggests that such amplification is a result of a phenotypic shift in the non-GSC population to a GSC-like state in the presence of TMZ. The newly converted GSC population expresses markers associated with pluripotency and stemness, such as CD133, SOX2, Oct4, and Nestin. Furthermore, we show that intracranial implantation of the newly converted GSCs in nude mice results in a more efficient grafting and invasive phenotype. Taken together, these findings provide the first evidence that glioma cells exposed to chemotherapeutic agents are able to interconvert between non-GSCs and GSCs, thereby replenishing the original tumor population, leading to a more infiltrative phenotype and enhanced chemoresistance. This may represent a potential mechanism for therapeutic relapse.
Glioblastoma (GBM) is the most common, and aggressive, primary brain tumor in adults. With a median patient survival of less than two years, GBM represents one of the biggest therapeutic challenges of the modern era. Even with the best available treatment, recurrence rates are nearly 100% and therapeutic options at the time of relapse are extremely limited. Nivolumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody, has provided significant clinical benefits in the treatment of various advanced cancers and represented a promising therapy for primary and recurrent GBM. CheckMate 143 (NCT 02017717) was the first large randomized clinical trial of PD pathway inhibition in the setting of GBM, including a comparison of nivolumab and the anti-VEGF antibody, bevacizumab, in the treatment of recurrent disease. However, preliminary results, recently announced in a WFNOS 2017 abstract, demonstrated a failure of nivolumab to prolong overall survival of patients with recurrent GBM, and this arm of the trial was prematurely closed. In this review, we discuss the basic concepts underlying the rational to target PD pathway in GBM, address implications of using immune checkpoint inhibitors in central nervous system malignancies, provide a rationale for possible reasons contributing to the failure of nivolumab to prolong survival in patients with recurrent disease, and analyze the future role of immune checkpoint inhibitors in the treatment of GBM.
Functional, tumor-specific CD8+ cytotoxic T lymphocytes drive the adaptive immune response to cancer. Thus, induction of their activity is the ultimate aim of all immunotherapies. Success of anti-tumor immunotherapy is precluded by marked immunosuppression in the tumor microenvironment (TME) leading to CD8+ effector T cell dysfunction. Among the many facets of CD8+ T cell dysfunction that have been recognized—tolerance, anergy, exhaustion, and senescence—CD8+ T cell senescence is incompletely understood. Naïve CD8+ T cells require three essential signals for activation, differentiation, and survival through T-cell receptor, costimulatory receptors, and cytokine receptors. Downregulation of costimulatory molecule CD28 is a hallmark of senescent T cells and increased CD8+CD28− senescent populations with heterogeneous roles have been observed in multiple solid and hematogenous tumors. T cell senescence can be induced by several factors including aging, telomere damage, tumor-associated stress, and regulatory T (Treg) cells. Tumor-induced T cell senescence is yet another mechanism that enables tumor cell resistance to immunotherapy. In this paper, we provide a comprehensive overview of CD8+CD28− senescent T cell population, their origin, their function in immunology and pathologic conditions, including TME and their implication for immunotherapy. Further characterization and investigation into this subset of CD8+ T cells could improve the efficacy of future anti-tumor immunotherapy.
Hemorrhagic stroke accounts for only 10% to 15% of all strokes; however, it is associated with devastating outcomes. Extension of intracranial hemorrhage (ICH) into the ventricles or intraventricular hemorrhage (IVH) has been consistently demonstrated as an independent predictor of poor outcome. In most circumstances the increased intracranial pressure and acute hydrocephalus caused by ICH is managed by placement of an external ventricular drain (EVD). We present a systematic review of the literature on the topic of EVD in the setting of IVH hemorrhage, articulating the scope of the problem and prognostic factors, clinical indications, surgical adjuncts, and other management issues.
One of the hallmark features of glioblastoma multiforme (GBM), the most common adult primary brain tumor with a very dismal prognosis, is the accumulation of CD4+CD25+Foxp3+ regulatory T cells (Tregs). Regulatory T cells (Tregs) segregate into two primary categories: thymus-derived natural Tregs (nTregs) that develop from the interaction between immature T cells and thymic epithelial stromal cells, and inducible Tregs (iTregs) that arise from the conversion of CD4+FoxP3− T cells into FoxP3 expressing cells. Normally, these Treg subsets complement one another’s actions by maintaining tolerance of self-antigens, thereby suppressing autoimmunity, while also enabling effective immune responses toward non-self-antigens, thus promoting infectious protection. However, Tregs have also been shown to be associated with the promotion of pathological outcomes, including cancer. In the setting of GBM, nTregs appear to be primary players that contribute to immunotherapeutic failure, ultimately leading to tumor progression. Several attempts have been made to therapeutically target these cells with variable levels of success. The blood brain barrier-crossing chemotherapeutics, temozolomide, and cyclophosphamide (CTX), vaccination against the Treg transcriptional regulator, FoxP3, as well as mAbs against Treg-associated cell surface molecules CD25, CTLA-4, and GITR are all different therapeutic approaches under investigation. Contributing to the poor success of past approaches is the expression of indoleamine 2,3-dioxygenase 1 (IDO), a tryptophan catabolizing enzyme overexpressed in GBM, and critically involved in regulating tumor-infiltrating Treg levels. Herein, we review the current literature on Tregs in brain cancer, providing a detailed phenotype, causative mechanisms involved in their pathogenesis, and strategies that have been used to target this population, therapeutically.
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