Cells and soluble mediators of the tumor microenvironment

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Immune cell surveillance by an array of cell types not only ensures the maintenance of tissue structure and function but also is responsible for mounting acute inflammatory responses that protect the host from pathogens. During an insult resulting from infection or trauma, granulocytes are recruited to sites of acute inflammation to confine tissue damage and initiate healing. Leukocytes, such as macrophages and other cell types, migrate from the peripheral circulation to sites of injury to remove damaged cells and debris, which facilitates resolution of inflammation. Finally, fibroblasts are required for extracellular matrix deposition and vascular endothelial cells mediate angiogenesis—both processes required for tissue repair.

A large body of literature has reported that malignancy is frequently associated with chronic, persistent, pathological inflammation [1–3]. Moreover, with respect to cancer progression, several investigations have revealed that specific populations of immune cells possess either anti-tumorigenic properties or the ability to promote tumorigenesis. Disease progression may therefore depend on the balance of these cell subsets and the milieu of soluble mediators.

We recently compiled a handbook of antibody-based tools for evaluating tumor-related inflammation (download it at thermofisher.com/tumorinflammation-hb). Table 1 (excerpted from this handbook) provides an overview of proinflammatory proteins associated with leukocytes in the tumor microenvironment, along with antibody- based tools for a variety of experimental applications.

Dissecting the role of different cell types in tumor-related inflammation

The inflammatory tumor microenvironment comprises a wide variety of cell types (Figure 1). Recent studies of cancer stroma and immune system–based biomarker profiles in solid tumors indicate that survival or response to cancer therapy may either be positively or negatively correlated with the ratios of specific cell populations. For example, research studies of human breast cancer demonstrated that stromal cancer-associated fibroblasts (CAFs) contribute to the tumorigenic microenvironment and are negatively correlated with survival. These cells produce the chemokine stromal cell–derived factor 1 (SDF-1, also known as CXCL12)—a strong lymphocyte and macrophage chemoattractant—which signals through the receptor CXCR4 to promote tumor cell growth, invasion, and tumor angiogenesis [4–6]. Published reports have established that the presence of macrophages

Published reports have established that the presence of macrophages in a number of different cancers correlates with increased vascular density and a poor clinical outcome, and the presence of tumor-associated macrophages (TAMs) supports tumor growth. Furthermore, a cell signature consisting of a high level of macrophages and CD4+ T cells relative to low levels of tumor-specific CD8+ cytotoxic T lymphocytes (CTLs) was predictive of reduced survival. In addition, various studies employing mouse models suggest that manipulation of the tumor microenvironment by depletion of mammary TAMs—cells that promote inflammation and inhibit tumoricidal responses—may enhance the response to chemotherapy and augment the activity of tumor-specific CTLs [5].

The field of tumor immunology recently realized great successes with the Food and Drug Administration (FDA) approval of three novel biotherapeutic agents designed to boost CTL-mediated rejection of solid tumors. Years of work in cell immunology and cancer research enabled the development of ipilimumab, an anti–CTLA-4 monoclonal antibody for the treatment of melanoma, and pembrolizumab and nivolumab, two anti–PD-1 monoclonal antibodies for the treatment of metastatic melanoma and metastatic non-small cell lung carcinoma (NSCLC), respectively. New strategies designed to enhance anti-tumor immune responses and reduce pro-tumorigenic conditions are under intense investigation [7,8].

Representation of cell components of the inflammatory tumor microenvironment
Figure 1. Representation of cell components of the inflammatory tumor microenvironment. Cells that reside within solid tumors—including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), T regulatory cells (Tregs), and other cells—actively suppress antigen-presenting cells such as dendritic cells and inhibit productive anti-tumor responses mediated by cytotoxic CD8+ T cells (CTLs) and natural killer cells.

Antibody-based analysis of the tumor microenvironment

The role of antibodies in basic and translational research cannot be overstated. The ability to produce highly purified target-specific antibodies has made it possible to detect, quantify, and observe the ways in which specific proteins function within tissue, cells, and extracellular compartments. The use of research antibodies has an important place in the greater context of powerful preclinical cancer models, genomics and proteomics tools, and cellular imaging modalities that continue to fuel advances in basic science and medicine.

Characterization of cell populations that frequently infiltrate solid tumors relies, in large part, on the ability to perform these procedures: (1) liberate cells from solid tumors for analysis by flow cytometry; (2) detect cells in tissues by histology, immunohistochemistry, and immunofluorescence; and (3) detect signature cytokines and growth factors linked to tumor-related inflammation using various soluble-protein detection methods such as enzyme-linked immunosorbent assays (ELISAs) and western blots. Table 1 provides an overview of key features attributed to cell populations commonly associated with the tumor microenvironment, and provides a list of representative antibodies and ELISA kits that may be used for protein and cell analysis in a range of applications. In our handbook Antibody-based tools for evaluating tumor-related inflammation (download it at thermofisher.com/tumorinflammation-hb), we provide links to antibody-based tools as well as access to detailed protocols for a number of experimental techniques, including western blot, ELISA, immunofluorescence analysis, flow cytometry, and more.

Table 1. Proinflammatory proteins associated with leukocytes of the tumor microenvironment.

Protein Source Antibody Cat. No. ELISA Cat. No. Functions in linking inflammation to cancer
IL-6 MDSCs, TAMs 700480 KHC0061
  • Promotes tumor growth
IL-8 MDSCs, TAMs 710256 KHC0081
  • Enhances proliferation, migration, and angiogenesis
IL-10 MDSCs, TAMs, Tregs 710170 KHC0101
  • Anti-inflammatory
  • Downregulates expression of Th1 cytokines and co-stimulatory molecules on macrophages
IL-17 Th17 cells PA1-84183 EHIL17A
  • Associated with angiogenesis and poor prognosis
IL-21 Th17 cells 710141 EHIL21
  • Associated with tumor development
IL-22 Th17 cells 701031 EHIL22
  • Promotes differentiation of Th17 cells
TNF-α> Macrophages, monocytes, neutrophils, T cells, NK cells 710288 KHC3011
  • Induces DNA damage and inhibits DNA repair
  • Promotes tumor growth
  • Induces angiogenic factors
GM-CSF Macrophages, T cells, mast cells, NK cells, endothelial cells, fibroblasts 701136 KHC2011
  • Activates macrophages
M-CSF Endothelial cells, fibroblasts PA1-20182 EHCSF1
  • Controls production, differentiation, and function of macrophages

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