TheCNS is equipped with a sophisticated, native immune system that participates in the surveillance of foreign bodies at its interface with the periphery.1The outermost layer of the brain’s protective sheath is the dura mater. Because of its unique anatomy and immunological landscape, the dura is integral to immunosurveillance within the CNS. First, it contains its own native population of immune cells, many of which lie in parallel to dural venous sinuses.2Second, the dura interacts with resident immune cells within the bone marrow of the skull’s inner table through microscopic vascular channels.3第三,硬脑膜的脉管系统包含开窗术s that allow extravasation of material into the surrounding tissue.1Fourth, the dura is home to its own lymphatic system that drains to deep cervical lymph nodes, serving as an efferent immunological pathway in addition to its afferent innate/adaptive functions.1,4Lastly, the dura has been shown to promote both proinflammatory and protumorigenic/anti-inflammatory milieus.1,5Dural metastases are found in approximately 8%–9% of systemic cancer patients on autopsy.6,7硬脑膜的接口与转移性肿瘤细胞an imperative point of study to better understand the vulnerabilities to CNS barrier penetration and reprogramming of the resident immune landscape into one that sustains a tumor microenvironment (TME). There have been significant advances in immunotherapy for non-CNS solid malignancies. However, it is unclear how these therapies will translate to the CNS. The purpose of this review is to describe the dural barrier anatomy and resident immune population, features that participate in the metastatic cascade. Finally, we highlight the translational aspects of dural immunology and its ramifications for the treatment of CNS metastasis with immunotherapy.
Dura Anatomy, Function, and Immunological Landscape
While formerly described as an "immune-privileged" area, recent studies have elucidated the immunological landscape of the CNS, which consists of both innate and adaptive resident immune cells, many of which are native to the dura.8From superficial to deep, the meningeal layer consists of the dura mater, arachnoid mater, and pia mater, of which the latter two are collectively referred to as the leptomeninges.4The dura differs from the leptomeningeal layer in that its vasculature lacks tight junctions, with fenestrations that allow immunological surveillance and exchange of material between the peripheral circulation and that of the CNS.1,8,9For example, CD4+ T cells participate in surveillance by working in concert with perivascular macrophages to probe the surrounding tissue for unwanted foreign bodies.10Together, the meningeal immune cell landscape consists of neutrophils, dendritic cells, macrophages (distinct from macrophages in the parenchyma), monocytes, immune lymphoid cells, natural killer cells, T cells, B cells, and plasma cells.8–10Single-cell RNA sequencing of the dura mater has unveiled its diverse resident immune cell population, with cells from both lymphoid and myeloid lineages.11The dura’s unique architecture, when compared with that of the leptomeninges, functions both as an immune barrier and access pathway for foreign pathogens and cancer cells. Moreover, the dura is the only CNS compartment to contain both resident immune cells and an active glymphatic system that drains into deep cervical lymph nodes (Fig. 1A).4
A:Dural and leptomeningeal immune landscape in the steady state, depicting resident immune cells, including B cells, T cells, dendritic cells, and macrophages.B:Meningeal proinflammatory immune response in the setting of metastatic tumor cells, here depicting the release of proinflammatory cytokines and the recruitment of a cytotoxic T cell response with lymphatic drainage.C:Meningeal immunosuppressive state in the setting of immunomodulating and suppressive metastatic tumor cells that stimulate Tregs and inhibitory macrophages. DC = dendritic cell; ILC = innate lymphoid cell; Mi= inhibitory macrophage; MC = monocyte. Illustration from the National Institutes of Health/Office of Research Services/Medical Arts, Alan Hoofring.
In addition to a native vascular bed in the dura mater, there is also a lymphatic network with a noncontinuous basement membrane that lies in parallel to the dural venous sinuses.8,12–15This lymphatic network can be visualized around these sinuses, the cribriform plate, and the middle meningeal artery on postgadobutrol T2-weighted FLAIR MR imaging, alongside 3D rendering.16This network has also been described in human cadaveric studies, showing intradural vascular-like channels that are positive for lymphatic markers Lyve-1 and podoplanin.17The contents of this dural lymphatic drainage instigate an inflammatory response both peripherally and within the CNS itself. Arachnoid granulations, found at the dura-brain border, have been purported as adhesive pockets where CNS antigens are trapped and immune cells are sequestered, functioning like "lymph nodes" of the CNS.18
Under normal conditions, the dura interacts with the overlying bone marrow of the skull through the diploic vein–dural vessel interface.10This interface has been studied in a murine model, where myeloid cells have been shown to migrate through and traverse small vascular beds that connect the inner skull cortex to the dura mater, thus allowing for entry into the meninges.3Neutrophils and monocytes have been reported to enter the meninges from adjacent skull or vertebral bone, and hematogenous malignancies have been shown to access the leptomeninges using a similar route.10,19This evidence invites the question of whether or not solid malignancies could similarly exploit these vascular beds to enter into the subarachnoid space.20Herisson et al.3confirmed the presence of channels connecting skull bone marrow to dural vasculature using electron microscopy in adult mice; the investigators also collected patient-derived craniectomy specimens following operative cases, in which they found similar vascular channels.3In their murine models in the setting of stroke, they found movement of myeloid cells from the inner skull cortex to its interface with the dura mater, further supporting the notion that the skull bone marrow functions as a source of immune cells for the brain, enabled through its vascular connection with the meninges.3This may, in part, be due to the vasculature becoming leaky and susceptible to immune cell extravasation during an inflammatory state such as stroke or infection, as leukocytes have been identified in dural perivascular spaces of stroke-induced mice.3
Additionally, B cells inhabiting the meninges come from both the adjacent skull bone marrow and the dural venous sinuses.19,21Antigens in the vicinity of these sinuses are identified by antigen-presenting cells (i.e., monocytes and dendritic cells) and presented to patrolling T cells.22In murine models, B-cell progenitors that are ordinarily only found in the bone marrow have been identified in the dura, which further demonstrates the interconnectedness of the skull bone marrow and the dura mater as a pathway for peripheral-to-CNS communication.23Schafflick et al.23offered another perspective based on experiments in rodents, finding that the dura is home to B-cell progenitors onward throughout their maturation and activation, and that these dural-resident B cells undergo development at the site of the dura and are not exclusively derived from the nearby skull bone marrow or from the peripheral circulation.23
Dura Mater Contribution to the Cerebral Metastatic Cascade
The architecture of the dural vasculature and lymphatic network make this layer vulnerable to the inward passage of large molecules, and it is of particular interest how resident immune cells within this neuroanatomical framework cooperate in brain metastasis.9The most common brain metastases are from lung, breast, and skin (melanoma) cancers.24Generally, the pathway of metastasis involves tumor cell detachment from the primary tumor and hematogenous spread to distant sites after intravasation into local blood vessels, following which, cancer cells reach CNS capillaries and extravasate into the surrounding tissue.24A few mechanisms have been studied by which metastatic cancer cells accomplish extravasation and invasion into the CNS. First, intravital imaging, including multiphoton laser scanning microscopy, has been used in mice to characterize the metastatic cascade into the CNS. These studies showed evidence of hematogenous spread of circulating tumor cells, with cells arresting in the microvasculature at branch points and with subsequent extravasation, promoting perivascular growth through angiogenesis.20,25This mechanism has been shown previously in melanoma and lung carcinoma cell lines.25Second, there is evidence for direct extension of cancer cells from the overlying calvarial bone marrow into the CNS. Yao et al. showed that acute lymphoblastic leukemia cells, which metastasize to the leptomeninges, use laminin-enriched emissary vessels that bridge directly between the calvarial bone marrow and the subarachnoid space.26Importantly, these cancer cells express α6 integrin, which is a receptor for laminin, and this ligand-receptor interaction has been suggested to facilitate the exploitation of neural migratory pathways by acute lymphoblastic leukemia cells for invading the CNS.26Third, it has been suggested that malignant cancer cells may be able to evade the process of entry into and extravasation from CNS vasculature, instead using abluminal vessel surfaces to enter the CNS’s subarachnoid space directly.20,27
A retrospective review by Nayak et al.28evaluated intracranial dural metastases in 122 patients, with the most common primary sites being breast and prostate cancers (which oftentimes metastasize to bone), head and neck cancers (which can invade the skull base and dura), as well as leukemia and lymphoma (which spread hematogenously).28In fact, 61% of patients had intradural metastases that directly spread from the overlying skull, and 33% of patients had intradural metastases that were hematogenously seeded.28Surgical seeding was also postulated as a likely source of intradural metastases, given that many were located at previous resection sites of the brain.28The important element is the route of spread, as we have discussed how vascular beds between the inner table of the skull are instrumental in skull–dural immune cell interaction, as are dural vascular fenestrations and venous sinus resident immune cells in surveilling dural tissue and allowing pathogen entry. Given that the dura lies outside of the blood-brain barrier, it is consequently vulnerable to hematogenously spread metastases.28Interestingly, the median survival of patients with intradural metastases was found to be greater than that reported for patients with brain parenchymal metastases (9.5 vs 4–6 months) and those with leptomeningeal metastases (9.5 vs 2 months).28
Immunomodulation Within the Tumor Microenvironment
Once metastases invade the CNS, they engage with a dynamic resident stromal population, stimulating differential proinflammatory and immunosuppressive programs (Fig. 1BandC). Metastatic melanoma is known for its propensity to spread to the CNS, and it has a tendency to metastasize into the meningeal and ventricular regions.29Notably, asymptomatic patients with melanoma cerebral metastasis show a clinical benefit rate of 57% with anti–PD-1/CTLA-4 combination therapy.30There is evidence that the efficacy of anti–PD-1/CTLA-4 immunotherapy is dependent on dural lymphatics. Hu et al.31showed that the response of anti–PD-1/CTLA-4 checkpoint therapy in murine B16 intracranial melanoma was significantly reduced with disruption of the dorsal dural lymphatic vessels (DDLVs).31Furthermore, impairment of the DDLVs attenuated the immunotherapy-mediated CD8+ proliferation, enhanced CD8+ interferon-γ production, and suppressed CD4+Foxp3+Treg (regulatory T) cells.31The proposed mechanism is that antigen-stimulated dendritic cells are unable to traffic to cervical lymph nodes without DDLVs and are thus unable to propagate an antitumor-specific immune response.31Checkpoint inhibitor immune responses are potentiated by VEGF-C overexpression.31,32This effect is dependent on intact DDLVs, as well as CCL21/CCR7-facilitated T cell homing.31
A study of more than 80 tissue samples of melanoma brain metastases found two different clusters of tumor, distinguished by genes for immune cell signaling. One cluster expressed genes that signal immune cell infiltration of tumor, including CD8+ T cells, dendritic cells, and cytotoxic lymphocytes.33This cluster was associated with increased patient survival compared with the other cluster.33However, metastatic melanoma cells have also been shown to cultivate an immunosuppressive TME by sequestering anti-inflammatory mediators, including M2 macrophages, Tregs, cancer-associated fibroblasts, and myeloid-derived suppressor cells.34Interestingly, however, metastatic melanoma cells initially promote a proinflammatory environment by reprogramming astrocytes via amyloid beta protein.33–35Astrocytes produce inflammatory cytokines like transforming growth factor (TGF)–β2 and IL-23, the latter of which leads to matrix metalloproteinase degradation of the extracellular matrix and invasion of metastatic cells into the brain parenchyma.34Adaptive immune responses, such as T cell costimulation, can also be suppressed; CD80 and CD86, which participate in T cell costimulation, are reduced in number.34Additionally, CXCL12 is a chemokine that plays a role in T cell egress from the TME; conversely, downregulation of CXCL12 has been shown to promote retention of T cells in the tumor microenvironment, which allows them to participate in antitumor control, rather than migrating out of the TME and into the dural lymphatic system.36CXCL12 has been shown to be highly expressed in calvarial dura.5Moreover, in a study by Szerlip et al.,5RNA sequencing of mouse dural fibroblasts revealed a high expression of growth factors and cytokines that are known to be involved in cancer metastasis and progression, including BMP4, FGF2, TGF-α, TGF-β1–3, VEGF-α, VEGF-β, and PDGF-β.5In the same study, the authors demonstrated that dura-conditioned media induced a significant increase in the proliferation and survival of prostate carcinoma (DU145) and breast carcinoma (MDA-MB-231) lines.5Altogether, we have demonstrated that the dura plays a significant role in cerebral metastasis through immunological trafficking and secreted factors.
Translational Implications of Dural Contributions to the Metastatic Cascade
With current knowledge and understanding of the CNS’s immune landscape and the immunomodulative functions of tumor cells, immunotherapy has transformed treatment approaches.37Unlike chemotherapy, which functions to eradicate cells, immunotherapy aims to increase the immune response against cancer.38The dura houses a variety of resident immune cells, including macrophages, lymphocytes, and dendritic cells, among various others from both lymphoid and myeloid lineages.8,11,22,39In the context of cancer, immunotherapy can operationalize and bolster this immunological presence to overcome otherwise immunosuppressive tumor cells.
A number of different receptor ligands targeted by immunotherapy include PD-1/PD-L1, CTLA-4/B7, and TIGIT/CD96.38These receptor-ligand pairs are expressed on a variety of cell types, including CD4+ and CD8+ T cells, natural killer B cells, and dendritic cells; overall, these pathways are capable of promoting tumor escape and immunosuppression.38As mentioned previously, metastatic melanoma cells foster an immunosuppressive tumor microenvironment, expressing factors like PD-L1.34Immunotherapeutic agents include anti-PD-1 and anti-PD-L1 monoclonal antibodies, as well as anti-cytotoxic T lymphocyte–associated antigen-4 (anti–CTLA-4).34Pembrolizumab (a PD-1 inhibitor), in combination with anti–CTLA-4 drugs, has been shown to be more effective than monoimmunotherapy, and dual immune checkpoint inhibitors have become the standard of care for treating melanoma brain metastases.33These checkpoint inhibitors restore an immune-responsive, proinflammatory tumor microenvironment that overcomes the immunosuppressive effects of tumor-secreted cytokines and growth factors; immunotherapies achieve this outcome by suppressing Tregs and stimulating cytotoxic T lymphocytes toward antitumor activity.40In patients who receive immune checkpoint inhibitor treatment, the population of CD8+ T cells in the CSF has been shown to increase after treatment administration, with levels being significantly higher than pretreatment samples.41
Additionally, Chauvin et al.42investigated T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) in metastatic melanoma patients. In these patients, the TIGIT receptor was found on tumor-infiltrating CD8+ T cells and on Tregs, with the downstream effect of immunosuppression in the TME.42One mechanism of this immunosuppression is TIGIT inhibition of T cells from proliferating and producing cytokines.42PD-1受体也coexpressed TIGIT on CD8+ tumor-infiltrating cells in metastatic melanoma human cell lines, and the blockade of both of these receptors can restore the antitumor function of tumor-infiltrating lymphocytes in the TME.42The blockade of TIGIT and PD-1 has been shown to be beneficial in other cancer types as well, including glioblastoma (GBM). In a GBM mouse model, inhibition of both TIGIT and PD-1, compared with either by itself, was shown to increase mouse survival time and levels of tumor-infiltrating lymphocytes.43Dismal prognosis and tumor advantage conferred by TIGIT and PD-1 have been seen in other cancer types also, including non–small cell lung cancer.44Overall, immunoregulatory mediators, such as TIGIT and PD-1, are capable of immunosuppressive activity within the TME, and blockade of both has been highlighted as a promising therapeutic aim.
Moreover, the RAMP1-CALCRL-CGRP (calcitonin gene-related peptide) activation pathway has been implicated in modulating the meningeal immune cell landscape by suppressing overall immune cell response to bacterial invasion.45CGRP is involved in migraine pathology, with CGRP inhibitors now a viable preventative treatment option for migraines; CGRP has also been shown to enhance expression levels of acetylcholine receptors (AChRs) in the brain.45,46Pinho-Ribeiro et al.45investigated the neuroimmune axis of CGRP’s activation pathway in the setting ofStreptococcus pneumoniaeandStreptococcus agalactiaeinfections in mice. These bacteria were capable of directly eliciting CGRP release from trigeminal neurons that innervate the dura mater.45CGRP was found to limit the response of dural-resident immune cells, functioning as an anti-inflammatory modulator via increased IL-10 expression during infection.45Infection led to transcriptional alterations in myeloid immune cell populations, with macrophages in particular being affected and their function suppressed by CGRP/RAMP1 signaling, thus allowing for bacterial invasion and meningitis.45Loss of RAMP1 was then found to improve the protective meningeal defenses against infection.45Interestingly, the upregulation of AChRs has also been found in areas of GBM infiltration, and as CGRP is known to enhance AChR expression and to function as an anti-inflammatory modulator, this invites the question of whether or not CGRP has a role in promoting a protumor microenvironment in the brain.45–47
Overall, immunotherapy offers a mechanism of overcoming the immunosuppressive tumor microenvironment induced by metastatic tumor types. Checkpoint inhibitors, particularly dual inhibitors, have been shown to be effective in treating brain metastases, in large part due to reversal of the immunosuppressive pathways in which metastatic tumor cells participate.33While the dura maintains an immune landscape of innate and adaptive immunity, it has also been shown to produce cytokines and growth factors involved in cancer and immune cell pathways. Treating brain metastases with immunotherapy can specifically target some of those pathways and switch the microenvironment from immunosuppressed to proinflammatory, to reverse a tumor’s evasion from the immune system.
Conclusions
最近的进步在解剖结构d immune landscape of the dura mater have dramatically changed neuroimmunology. The dura engenders an active glymphatic system that drains to deep cervical lymph nodes where antigen presentation occurs. This can then prompt a local dural inflammatory response in cases of neurotropic pathogens. We hypothesize that similar responses are present in cases of cerebral metastases but are fettered by the immunosuppressive nature of cancer. Immunotherapy may help to liberate these proinflammatory immune cells to eradicate metastatic disease in the dura mater and/or adjacent leptomeningeal space. Overall, we expect that future scientific advances will highlight the importance of the dura as a key neuroanatomical barrier in neuro-oncology within the next few years.
Acknowledgments
This work was supported by the Surgical Neurology Branch within the National Institute of Neurological Disorders and Stroke. We thank Alan Hoofring and Ethan Tyler in the NIH Medical Arts Design Section for their assistance with the illustration ofFig. 1. Dr. Ampie thanks Dorian McGavern, PhD, for his mentorship and guidance in learning meningeal neuro-immunology and dedicates this article to Andrew T. Parsa, MD, PhD.
Disclosures
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
Author Contributions
Conception and design: all authors. Acquisition of data: Cozzi. Analysis and interpretation of data: Ampie, Cozzi, Brown. Drafting the article: Ampie, Cozzi, Laws. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Ampie. Administrative/technical/material support: Ampie, Laws. Study supervision: Brown.
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