T lymphocytes facilitate brain metastasis of breast cancer by inducing Guanylate-Binding Protein 1 expression

Abstract

The discovery of genes and molecular pathways involved in the formation of brain metastasis would direct the development of therapeutic strategies to prevent this deadly complication of cancer. By comparing gene expression profiles of Estrogen Receptor negative (ER-) primary breast tumors between patients who developed metastasis to brain and to organs other than brain, we found that T lymphocytes promote the formation of brain metastases. To functionally test the ability of T cells to promote brain metastasis, we used an in vitro blood–brain barrier (BBB) model. By co-culturing T lymphocytes with breast cancer cells, we confirmed that T cells increase the ability of breast cancer cells to cross the BBB. Proteomics analysis of the tumor cells revealed Guanylate-Binding Protein 1 (GBP1) as a key T lymphocyte-induced protein that enables breast cancer cells to cross the BBB. The GBP1 gene appeared to be up-regulated in breast cancer of patients who developed brain metastasis. Silencing of GBP1 reduced the ability of breast cancer cells to cross the in vitro BBB model. In addition, the findings were confirmed in vivo in an immunocompetent syngeneic mouse model. Co-culturing of ErbB2 tumor cells with activated T cells induced a significant increase in Gbp1 expression by the cancer cells. Intracardial inoculation of the co-cultured tumor cells resulted in preferential seeding to brain. Moreover, intracerebral outgrowth of the tumor cells was demonstrated. The findings point to a role of T cells in the formation of brain metastases in ER- breast cancers, and provide potential targets for intervention to prevent the development of cerebral metastases.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1806-2) contains supplementary material, which is available to authorized users.

Comprehensive Analysis of the Expression and Prognosis for GBPs in Head and neck squamous cell carcinoma

“…A recent study showed that GBP1 may promote lung adenocarcinoma invasiveness by stimulate cell motility and via manage of GBP1 expression may development of new therapeutic ways for tumor 30 . GBP1 also found as a fetal T lymphocyte-induced protein that cause breast cancer cells to cross the blood-brain barrier 31 . Our results showed that higher mRNA expressions of GBP1 were found in HNSCC tissues, and that mRNA expression of GBP1 was significantly related with patients' cancer stages and abundance of immune infiltrates.…”

Guanylate-Binding Protein 1: An Emerging Target in Inflammation and Cancer

“…Similar results have been found in squamous head-and-neck cancers, where GBP1 expression correlates with disease stage and lymph node metastasis in patient samples (63,64). GBP1 expression has also been correlated with metastasis in both lung and breast cancers as well, where study of human lung cancer explants and brainmetastasizing breast cancer cells showed decreased migration in vitro upon GBP1 blockade and GBP1 expression correlated with disease progression in patients (54,65). Intriguingly, in breast cancer metastasis, it was found that GBP1 expression was induced in breast cancer cells by T-lymphocyte activity, showing that cancer-extrinsic processes may influence GBP1's context and function (54).…”

“…Cancer emerges from a complex interplay of mutational events and cell state transitions that are accompanied by interferonmediated inflammation and cytoskeletal reorganization which may involve GBP1 in the oncogenic process. The effects of GBP1 in cancer appear to be highly context-dependent, however, as its upregulation is associated with decreased progression in some cancer types, such as breast and colorectal cancer (51-53), but is linked with increased progression, metastasis, and treatment resistance in other cancer types, such as ovarian cancer and glioblastoma (17,54). Although GBP1 may exert these effects in a cancer-intrinsic manner by acting within cancer cells or via a cancer-extrinsic mechanism through microenvironment and immune activity, current literature does not yet distinguish clearly between these contributions and additional investigation is urgently needed.…”

“…GBP1 expression has also been correlated with metastasis in both lung and breast cancers as well, where study of human lung cancer explants and brainmetastasizing breast cancer cells showed decreased migration in vitro upon GBP1 blockade and GBP1 expression correlated with disease progression in patients (54,65). Intriguingly, in breast cancer metastasis, it was found that GBP1 expression was induced in breast cancer cells by T-lymphocyte activity, showing that cancer-extrinsic processes may influence GBP1's context and function (54). One aspect of this differential activity may be influenced by heterogeneous binding partners, such as the findings that GBP1 interacts directly with protooncogene serine/threonine kinase 1 (PIM1), a marker of disease progression and treatment resistance in ovarian and other cancers (66,67).…”

High neutrophil, low lymphocyte and hemoglobin unfavorably impact survival in non-small cell lung cancer patients with brain metastases

“…While the biologic basis of the relationship between posttreatment NLR and success of treatment is quite complex. It is true that lymphopenia is correlated with a poor prognosis, while a preclinical study found that activated T cells could facilitate BM through inducing an elevated expression of Guanylate-Binding Protein 1 (GBP1) by the cancer cells (26). Moreover, neutropenia increase the risk of infections.…”