Embracing rejection: Immunologic trends in brain metastasis

Farber, S. Harrison; Tsvankin, Vadim; Narloch, Jessica L.; Salama, April K.S.; Vlahović, Gordana; Blackwell, Kimberly; Kirkpatrick, John P.; Fecci, Peter E.

doi:10.1080/2162402x.2016.1172153

Cited by 35 publications

(27 citation statements)

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“…Encouraging results have emerged for tyrosine kinase inhibitors and monoclonal antibodies in subgroups of patients with BM (Table 4 ). As CNS immune-accessibility has become accepted, and immunotherapy (IT) gains greater understanding within trials for primary brain tumors, there is an increasing interest in immunotherapeutic approaches to BMs with immune checkpoint inhibitors ( 181 – 183 ) (Table 5 ).…”

Section: Chemotherapy and Targeted Therapiesmentioning

confidence: 99%

Mechanisms and Therapy for Cancer Metastasis to the Brain

2018

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Advances in chemotherapy and targeted therapies have improved survival in cancer patients with an increase of the incidence of newly diagnosed brain metastases (BMs). Intracranial metastases are symptomatic in 60–70% of patients. Magnetic resonance imaging (MRI) with gadolinium is more sensitive than computed tomography and advanced neuroimaging techniques have been increasingly used in the detection, treatment planning, and follow-up of BM. Apart from the morphological analysis, the most effective tool for characterizing BM is immunohistochemistry. Molecular alterations not always reflect those of the primary tumor. More sophisticated methods of tumor analysis detecting circulating biomarkers in fluids (liquid biopsy), including circulating DNA, circulating tumor cells, and extracellular vesicles, containing tumor DNA and macromolecules (microRNA), have shown promise regarding tumor treatment response and progression. The choice of therapeutic approaches is guided by prognostic scores (Recursive Partitioning Analysis and diagnostic-specific Graded Prognostic Assessment-DS-GPA). The survival benefit of surgical resection seems limited to the subgroup of patients with controlled systemic disease and good performance status. Leptomeningeal disease (LMD) can be a complication, especially in posterior fossa metastases undergoing a “piecemeal” resection. Radiosurgery of the resection cavity may offer comparable survival and local control as postoperative whole-brain radiotherapy (WBRT). WBRT alone is now the treatment of choice only for patients with single or multiple BMs not amenable to surgery or radiosurgery, or with poor prognostic factors. To reduce the neurocognitive sequelae of WBRT intensity modulated radiotherapy with hippocampal sparing, and pharmacological approaches (memantine and donepezil) have been investigated. In the last decade, a multitude of molecular abnormalities have been discovered. Approximately 33% of patients with non-small cell lung cancer (NSCLC) tumors and epidermal growth factor receptor mutations develop BMs, which are targetable with different generations of tyrosine kinase inhibitors (TKIs: gefitinib, erlotinib, afatinib, icotinib, and osimertinib). Other “druggable” alterations seen in up to 5% of NSCLC patients are the rearrangements of the “anaplastic lymphoma kinase” gene TKI (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib). In human epidermal growth factor receptor 2-positive, breast cancer targeted therapies have been widely used (trastuzumab, trastuzumab-emtansine, lapatinib-capecitabine, and neratinib). Novel targeted and immunotherapeutic agents have also revolutionized the systemic management of melanoma (ipilimumab, nivolumab, pembrolizumab, and BRAF inhibitors dabrafenib and vemurafenib).

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Section: Chemotherapy and Targeted Therapiesmentioning

confidence: 99%

Mechanisms and Therapy for Cancer Metastasis to the Brain

2018

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“…Immunotherapy is emerging as a promising anti-cancer treatment and is now part of the standard of care for certain advanced cancers including melanoma and non-small cell lung carcinoma [ 1 ]. Encouraging results from recent studies suggest that intracranial lesions located beyond the blood-brain barrier may also be targeted by the immune system [ 2 – 5 ]. However, patients with intracranial lesions are frequently provided corticosteroids before commencing immunotherapy to combat cerebral edema and reduce symptom burden.…”

Section: Introductionmentioning

confidence: 99%

Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy

Giles

Hutchinson

Sonnemann

et al. 2018

j. immunotherapy cancer

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342

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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.

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“…The latter is dependent on many factors and the cell composition in the TME. The brain naturally constitutes an immune suppressive microenvironment to prevent fatal neurotoxicity, potentially resulting in the exhaustion and inactivation of T cells in primary brain tumors (141). Moreover, it has been demonstrated with different BrM mouse models, that the number of FOXP3 + T regulatory cells (Tregs) is increased during BrM progression.…”

Section: Introductionmentioning

confidence: 99%

Microenvironmental Regulation of Tumor Progression and Therapeutic Response in Brain Metastasis

et al. 2019

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Cellular and non-cellular components of the tumor microenvironment (TME) are emerging as key regulators of primary tumor progression, organ-specific metastasis, and therapeutic response. In the era of TME-targeted- and immunotherapies, cancer-associated inflammation has gained increasing attention. In this regard, the brain represents a unique and highly specialized organ. It has long been regarded as an immunological sanctuary site where the presence of the blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCB) restricts the entry of immune cells from the periphery. Consequently, tumor cells that metastasize to the brain were thought to be shielded from systemic immune surveillance and destruction. However, the detailed characterization of the immune landscape within border-associated areas of the central nervous system (CNS), such as the meninges and the choroid plexus, as well as the discovery of lymphatics and channels that connect the CNS with the periphery, have recently challenged the dogma of the immune privileged status of the brain. Moreover, the presence of brain metastases (BrM) disrupts the integrity of the BBB and BCB. Indeed, BrM induce the recruitment of different immune cells from the myeloid and lymphoid lineage to the CNS. Blood-borne immune cells together with brain-resident cell-types, such as astrocytes, microglia, and neurons, form a highly complex and dynamic TME that affects tumor cell survival and modulates the mode of immune responses that are elicited by brain metastatic tumor cells. In this review, we will summarize recent findings on heterotypic interactions within the brain metastatic TME and highlight specific functions of brain-resident and recruited cells at different rate-limiting steps of the metastatic cascade. Based on the insight from recent studies, we will discuss new opportunities and challenges for TME-targeted and immunotherapies for BrM.

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Embracing rejection: Immunologic trends in brain metastasis

Cited by 35 publications

References 100 publications

Mechanisms and Therapy for Cancer Metastasis to the Brain

Mechanisms and Therapy for Cancer Metastasis to the Brain

Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy

Microenvironmental Regulation of Tumor Progression and Therapeutic Response in Brain Metastasis

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