Cancer Immunotherapy Getting Brainy: Visualizing the Distinctive CNS Metastatic Niche to Illuminate Therapeutic Resistance

Abstract

The advent of cancer immunotherapy (CIT) and its success in treating primary and metastatic cancer may offer substantially improved outcomes for patients. Despite recent advancements, many malignancies remain resistant to CIT, among which are brain metastases, a particularly virulent disease with no apparent cure. The immunologically unique niche of the brain has prompted compelling new questions in immuno-oncology such as the effects of tissue-specific differences in immune response, heterogeneity between primary tumors and distant metastases, and the role of spatiotemporal dynamics in shaping an effective anti-tumor immune response. Current methods to examine the immunobiology of metastases in the brain are constrained by tissue processing methods that limit spatial data collection, omit dynamic information, and cannot recapitulate the heterogeneity of the tumor microenvironment. In the current review, we describe how high-resolution, live imaging tools, particularly intravital microscopy (IVM), are instrumental in answering these questions. IVM of pre-clinical cancer models enables short- and long-term observations of critical immunobiology and metastatic growth phenomena to potentially generate revolutionary insights into the spatiotemporal dynamics of brain metastasis, interactions of CIT with immune elements therein, and influence of chemo- and radiotherapy. We describe the utility of IVM to study brain metastasis in mice by tracking the migration and growth of fluorescently-labeled cells, including cancer cells and immune subsets, while monitoring the physical environment within optical windows using imaging dyes and other signal generation mechanisms to illuminate angiogenesis, hypoxia, and/or CIT drug expression within the metastatic niche. Our review summarizes the current knowledge regarding brain metastases and the immune milieu, presents the current status of CIT and its prospects in targeting brain metastases to circumvent therapeutic resistance, and proposes avenues to utilize IVM to study CIT drug delivery and therapeutic efficacy in preclinical models that will ultimately facilitate novel drug discovery and innovative combination therapies.

Non-small cell lung cancer brain metastases and the immune system: From brain metastases development to treatment

“…Tumor associated macrophages (TAMs) also promote extravasation by expressing growth and survival factors and promoting angiogenesis. They also seem to be involved in the preparation of the perimetastatic niche [35]. This microenvironment then promotes migration of the circulating tumor cells into the brain parenchyma using site-specific chemokine secretion CXCR4/CXCL12 [36][37][38][39].…”

“…Once the metastasis occurs, the inflammatory macrometastasis includes the innate (microglia and macrophages) and adaptive immune systems [40]. In the perivascular niche brain metastatic cells activate and attract astrocytes and microglia (macrophage like cells) [35].…”

Overcoming Barriers of Age to Enhance Efficacy of Cancer Immunotherapy: The Clout of the Extracellular Matrix

“…Tumor-associated macrophages (TAMs) support tumorigenesis by promoting invasion and metastasis, tumor cell proliferation, and angiogenesis (Liu and Cao, 2014 ), while reducing the cytotoxicity and viability of T cells and NK cells (Edsparr et al, 2011 ). The pro-inflammatory (anti-tumorigenic) TAM, classically known as M1 polarized, develops in response to elevated levels of IFNγ/TNFα; the anti-inflammatory (pro-tumorigenic) TAM, classically known as M2 polarized, develops in response to elevated levels of IL-4/TGFβ (Owyong et al, 2017 ). Cytokines, produced through an inflammatory response, are used as predictive biomarkers for tumor development or regression (Martins et al, 2016 ).…”

“…CAR-T cell immunotherapy is indicated predominately for hematological indications (Owyong et al, 2017 ), and relies on engineering T cells with a tumor-specific antigen receptor that interacts with tumor-associated antigens (TAAs), independent of human leukocyte antigen (HLA) expression (Yu et al, 2017 ). This is of clinical relevance because one of the major impediments of TCR-based immunotherapy is TCR's recognition of antigens in an HLA-dependent pathway.…”

Combination of Immunotherapy and Brain Radiotherapy in Metastatic Melanoma: A Retrospective Analysis

“…A potential rationale could lie in the radiation-induced damage to the blood-brain barrier, leading to a better drug penetration in the central nervous system (CNS). More plausibly, RT could unmask cancer antigens, increasing the activity of drug-stimulated immune cells on distant localizations [9, 10]. This hypothesis may explain the so-called abscopal effect, that is, the evidence of disease response at nonirradiated sites during RT in patients with systemic malignancies.…”