Tumor Immune Microenvironment and Immunotherapy in Brain Metastasis From Non-Small Cell Lung Cancer

Abstract

Brain metastasis (BM), a devastating complication of advanced malignancy, has a high incidence in non-small cell lung cancer (NSCLC). As novel systemic treatment drugs and improved, more sensitive imaging investigations are performed, more patients will be diagnosed with BM. However, the main treatment methods face a high risk of complications at present. Therefore, based on immunotherapy of tumor immune microenvironment has been proposed. The development of NSCLC and its BM is closely related to the tumor microenvironment, the surrounding microenvironment where tumor cells live. In the event of BM, the metastatic tumor microenvironment in BM is composed of extracellular matrix, tissue-resident cells that change with tumor colonization and blood-derived immune cells. Immune-related cells and chemicals in the NSCLC brain metastasis microenvironment are targeted by BM immunotherapy, with immune checkpoint inhibition therapy being the most important. Blocking cancer immunosuppression by targeting immune checkpoints provides a suitable strategy for immunotherapy in patients with advanced cancers. In the past few years, several therapeutic advances in immunotherapy have changed the outlook for the treatment of BM from NSCLC. According to emerging evidence, immunotherapy plays an essential role in treating BM, with a more significant safety profile than others. This article discusses recent advances in the biology of BM from NSCLC, reviews novel mechanisms in diverse tumor metastatic stages, and emphasizes the role of the tumor immune microenvironment in metastasis. In addition, clinical advances in immunotherapy for this disease are mentioned.

Keywords: BM; NSCLC; PD-1 inhibitor; PD-L1 inhibitor; cancer; immunotherapy.

Figure 1

Mechanism of lung cancer brain metastasis. The changes of tumor microenvironment may promote some tumor cells to undergo epithelial-mesenchymal transition (EMT) process, to get the potential of metastasis and avoid apoptosis. These tumor cells escape from the primary tumor in the lung, invade the vessels, and circulate through the vessels, called circulating tumor cells (CTCs). Under the action of chemokines, CTCs reach the brain, cross the blood-brain barrier through rolling, adhesion and extravasation under the effect of E-ligand and integrin, undergo mesenchymal-epithelial transformation (MET) to regain the characteristic of the primary tumor, recover the characteristics of the primary tumor, and produce and adapt to the new tumor microenvironment. Angiogenesis is required for the growth of metastases. When pure oxygen diffusion is not sufficient for the tumor, the tumor gradually develops a hypoxic microenvironment and overexpress angiogenesis-stimulating factors, promoting the angiogenesis. The brain metastasis often happens in the gray and white matter junction and vascular border zones, where there is a longer mean transit times (MTT)of blood flow, providing more chance to overcome the blood-brain barrier.

Figure 2

Interactions of metastatic tumor cells with the brain microenvironment. After the tumor cells get into the CNS (central nervous system), according to the “seed and soil”, series of interactions happened between the tumor cells and the microenvironment in brain. Extensive research has shown that astrocytes play an important role in metastasis through matrix metalloproteinase 2 (MMP2), MMP9, exosome and gap junction, generally supports the growth and invasion. MMP2、MMP9 are associated with tumor growth. On the one hand, it could degrade components of the extracellular matrix and basement membrane, on the other hand, it helps to activate TGF-β and VEGF. Several studies have shown that after fusion of AST-generating exosomes with tumor cells, miRNAs contained in the exosomes cause tumor cells to under-express PTEN and further activate the PI3K/AKT/mTOR pathway, leading to more chemokine ligand 2(CCL2), promoting the growth of tumor. There are gap junctions composed of connexin 43 (Cx43) between tumor cell and astrocyte. Through the gap junction, astrocyte release cytokines such as IFNα and TNFα, activating STAT1 and NF-κB pathways, supporting tumor growth. At the same time, tumor cell could transfer cGAMP to astrocytes, activate the STAT3 pathways. Tumor-associated macrophages and microglia (TAMs), including bone marrow-derived macrophages (BMDMs) and microglia (MG), secret growth factors (EGF, IL6, TGF-β, IL-1β), contribute to the colonization. And the tumor cells release chemokines and cytokines (CSF-1, GM-CSF, MCP-1, HGF, SDF-1, CX3CL) to recruit TAMs towards the tumor cells. There are immune checkpoints expressed on T-cells, such as PD-1 and CTLA-4, which tumor cells could bind and deactivate T-cells, suppressing anti-tumor immunity. Checkpoint immunotherapy use antibodies to inhibit immune checkpoint to prevent the T-cell from deactivation and control the tumor.