Immunity, inflammation, and cancer

Abstract

Inflammatory responses play decisive roles at different stages of tumor development, including initiation, promotion, malignant conversion, invasion, and metastasis. Inflammation also affects immune surveillance and responses to therapy. Immune cells that infiltrate tumors engage in an extensive and dynamic crosstalk with cancer cells, and some of the molecular events that mediate this dialog have been revealed. This review outlines the principal mechanisms that govern the effects of inflammation and immunity on tumor development and discusses attractive new targets for cancer therapy and prevention.

Figure 1

Types of inflammation in tumorigenesis and cancer. Chronic inflammation associated with infections or autoimmune disease precedes tumor development and can contribute to it through induction of oncogenic mutations, genomic instability, early tumor promotion, and enhanced angiogenesis. Prolonged exposure to environmental irritants or obesity can also result in low-grade chronic inflammation that precedes tumor development and contributes to it through the mechanisms mentioned above. Tumor-associated inflammation goes hand in hand with tumor development. This inflammatory response can enhance neo-angiogenesis, promote tumor progression and metastatic spread, cause local immunosuppression, and further augment genomic instability. Cancer therapy can also trigger an inflammatory response by causing trauma, necrosis, and tissue injury that stimulate tumor re-emergence and resistance to therapy. However, in some cases, therapy-induced inflammation can enhance antigen presentation, leading to immune-mediated tumor eradication. Tumor promoting mechanisms are in red and anti-tumorigenic mechanisms are in green.

Figure 2

The multifaceted role of inflammation in cancer Inflammation acts at all stages of tumorigenesis. It may contribute to tumor initiation through mutations, genomic instability, and epigenetic modifications. Inflammation activates tissue repair responses, induces proliferation of premalignant cells, and enhances their survival. Inflammation also stimulates angiogenesis, causes localized immunosuppression, and promotes the formation of a hospitable microenvironment in which pre-malignant cells can survive, expand, and accumulate additional mutations and epigenetic changes. Eventually, inflammation also promotes metastatic spread. Mutated cells are marked with “X”. Yellow - stromal cells, Brown - malignant cells, Red - blood vessels, Blue - immune and inflammatory cells. Epithelial-mesenchymal transition, EMT; reactive oxygen species, ROS; reactive nitrogen intermediates (RNI)

Figure 3

Role of inflammation in tumor initiation and promotion A) Tumor initiation. Reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI) produced by inflammatory cells may cause mutations in neighboring epithelial cells. Also, cytokines produced by inflammatory cells can elevate intracellular ROS and RNI in pre-malignant cells. In addition, inflammation can result in epigenetic changes that favor tumor initiation. Tumor-associated inflammation contributes to further ROS, RNI and cytokine production. B) Tumor promotion. Cytokines produced by tumor infiltrating immune cells activate key transcription factors, such as NF-κB or STAT3, in pre-malignant cells to control numerous pro-tumorigenic processes, including survival, proliferation, growth, angiogenesis, and invasion. As parts of positive feed-forward loops, NF-κB and STAT3 induce production of chemokines that attract additional immune/inflammatory cells to sustain tumor-associated inflammation.

Figure 4

Immunosurveillance, tumor-promoting and therapy-induced inflammation. A) Balance between immunosurveillance and tumor promoting inflammation in the tumor microenvironment. Tumor promoting cytokines act on immune and malignant cells to tilt the balance toward tumor promotion. Tumor promoting immunity dampens immunosurveillance, which otherwise inhibits tumor growth. B) Therapy-induced inflammation. Various forms of therapy induce death (necrosis) of malignant cells resulting in the release of necrotic products and damage-associated molecular patterns (DAMPs) that activate cytokine-producing inflammatory cells. These cytokines activate pro-survival genes in residual cancer cells, rendering them resistant to subsequent rounds of therapy. However, in some cases, therapy-induced inflammation augments the presentation of tumor antigens and stimulates an anti-tumor immune response that improves the therapeutic outcome.