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Brain cancer induces systemic immunosuppression through release of non-steroid soluble mediators.

ABSTRACT: Immunosuppression of unknown aetiology is a hallmark feature of glioblastoma and is characterized by decreased CD4 T-cell counts and downregulation of major histocompatibility complex class II expression on peripheral blood monocytes in patients. This immunosuppression is a critical barrier to the successful development of immunotherapies for glioblastoma. We recapitulated the immunosuppression observed in glioblastoma patients in the C57BL/6 mouse and investigated the aetiology of low CD4 T-cell counts. We determined that thymic involution was a hallmark feature of immunosuppression in three distinct models of brain cancer, including mice harbouring GL261 glioma, B16 melanoma, and in a spontaneous model of diffuse intrinsic pontine glioma. In addition to thymic involution, we determined that tumour growth in the brain induced significant splenic involution, reductions in peripheral T cells, reduced MHC II expression on blood leucocytes, and a modest increase in bone marrow resident CD4 T cells. Using parabiosis we report that thymic involution, declines in peripheral T-cell counts, and reduced major histocompatibility complex class II expression levels were mediated through circulating blood-derived factors. Conversely, T-cell sequestration in the bone marrow was not governed through circulating factors. Serum isolated from glioma-bearing mice potently inhibited proliferation and functions of T cells both in vitro and in vivo. Interestingly, the factor responsible for immunosuppression in serum is non-steroidal and of high molecular weight. Through further analysis of neurological disease models, we determined that the immunosuppression was not unique to cancer itself, but rather occurs in response to brain injury. Non-cancerous acute neurological insults also induced significant thymic involution and rendered serum immunosuppressive. Both thymic involution and serum-derived immunosuppression were reversible upon clearance of brain insults. These findings demonstrate that brain cancers cause multifaceted immunosuppression and pinpoint circulating factors as a target of intervention to restore immunity.

SUBMITTER: Ayasoufi K

PROVIDER: S-EPMC7954397 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Myelodysplastic syndromes (MDS) are characterized by bone marrow failure due to disturbed bone marrow maturation. MDS is associated with increased risk of transformation to acute myeloid leukemia (AML) and features of immunological dysregulation. Serum levels of 47 soluble immune mediators were examined in samples derived from 49 MDS patients (35 low-risk and 14 high-risk) and 23 healthy adults. Our patients represent an unselected population-based cohort. The mediators included cytokines, soluble adhesion proteins, matrix metalloproteases, and tissue inhibitors of proteases. Levels were determined using Luminex assays. Patients were classified as low- and high-risk based on the international prognostic scoring system (IPSS) score. When comparing the serum levels of single mediators the MDS patients showed a relatively wide variation range for several mediators compared with healthy adults, especially interleukin 6 (IL-6), IL-8/CXCL8, CCL3, and CCL4. The high-risk patients had lower levels of epidermal growth factor (EGF), cluster of differentiation 40 ligand (CD40L), CCL5, CCL11, CXCL5, matrix metalloproteinase 1 (MMP-1), MMP-9, and tissue inhibitor of metalloproteinases 2 (TIMP-2) compared with low-risk patients. Unsupervised hierarchical cluster analysis visualized marked serum mediator profile differences between MDS patients; based on this analysis three patient subsets could be identified. The healthy adults were also included in this analysis and, as expected, they formed their own separate cluster, except for one outlier. Both low- and high-risk patients showed considerable heterogeneity with regard to serum profile, and this heterogeneity seems stable over time (one year follow-up). Finally, very few mediators differed between low- and high-risk patients, but hierarchical clustering based both on all mediators, as well as five selected mediators (EGF, CCL11, TIMP-2, MMP-1, and MMP-9) identified subsets of patients with significantly increased frequency of high-risk disease (χ-square test p = 0.0158 and p = 0.0148).

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Brain cancer induces systemic immunosuppression through release of non-steroid soluble mediators.

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