We identified references for this Review through searches of PubMed, Medline, and Google Scholar with the following appropriate free text and medical subject heading terms: “cancer”, “inflammation”, “inflammatory mediators”, “immune response”, “systemic inflammation”, “immune infiltrate”, “inflammasomes”, “signalling pathways”, “tumour necrosis”, “cytokines”, “inflammatory mediators”, “anti-inflammatory treatments”, “clinical trials”, “anti-cytokine”, “anti-angiogenesis”, and “cancer vaccines”.
ReviewCancer-related inflammation and treatment effectiveness
Introduction
Inflammation is recognised as a hallmark feature of cancer development and progression.1 Many cancer researchers, particularly those with a basic science or immunology focus, view cancer-related inflammation to pertain mainly to the local immune reaction found at the site of the tumour, which frequently precedes and contributes to its development. Clinicians view cancer-related inflammation as a sustained and perhaps inappropriate systemic reaction to malignancy that results in fevers, sweats, weight loss (the so-called B symptoms), and a range of other paraneoplastic symptoms. The view of cancer-related inflammation is further affected by the tumour stage (ie, early vs metastatic disease) and clinical circumstance (ie, good vs bad prognosis). Opposing effects of cancer-associated inflammation within the body, ranging from positive local effects, such as T-cell-mediated cytotoxicity in tumours leading to tumour inhibition,2, 3 through to detrimental systemic effects, such as B symptoms and cachexia,4, 5 create the biggest challenges to treatment.
In this Review, we consider local inflammation to be the local immune response, which encompasses tumour-derived and host-derived cytokines, small inflammatory protein mediators, and infiltrating immune cells acting in the local tumour microenvironment. For example, tissue injury and necrosis, external pathogen effects, or autoimmune disease can lead to a local immune response that mediates initiation and promotion of carcinogenesis. Systemic inflammation, on the other hand, likewise involves cytokines and small inflammatory proteins and immune cells; however, these mediators are present and detectable in the systemic circulation and give rise to the paraneoplastic symptoms observed in patients with cancer. There is substantial cross-talk between the mediators and cytokines in the local tumour microenvironment and systemic circulation (figure 1), and the targeting of cancer-related inflammation has the potential to favourably affect both compartments and thus benefit the patient.
Clearly, the tumour–host immune and inflammatory response is a complex interaction, with the key processes underlying this response far from fully understood. Nevertheless, these inflammatory responses already present a logical avenue for intervention, with non-selective and generally inexpensive anti-inflammatory drugs that have few toxicities being widely available and having the potential to improve outcomes. In this Review, we explore and describe these various inflammatory responses in the setting of established cancer to suggest potential intervention strategies aimed at favourably altering cancer-associated inflammation so as to improve patient outcomes. We give an overview of the main players in the local immune response, including tumour necrosis, inflammasomes, cytokines, chemokines, and transcription factors, and systemic inflammatory entities, such as acute-phase proteins and circulating immune cells (table 1); however, discussion of all aspects of tumour-related immunity is beyond the scope of this Review. With improved understanding of the factors implicated at both the local and systemic level, and their effects on the patient, the potentially targetable aspects will become clearer, which we will discuss in the second half of the Review.
Section snippets
Mediators of local inflammation
During the past decade, we have learned that within the tumour microenvironment, an intricate, coordinated network of cells communicate to form the local immune response.3 Cytokines, chemokines, and other small inflammatory proteins derived from either malignant or host cells (ie, stroma, endothelial cells, or immune cells) coordinate intracellular communication in the tumour microenvironment. The constant cross-talk between cells is essential for tumour growth, invasion, angiogenesis, and
Mediators of systemic inflammation
Systemic inflammation consists of circulating cytokines, small inflammatory proteins, circulating immune cells, and acute-phase proteins. Together, these mediators, particularly those associated with the innate inflammatory responses, produce the clinical symptoms that frequently mark the presence and progression of cancer.33 Circulating cytokines and small inflammatory proteins, such as chemokines and matrix-degrading proteins, perform similar functions in the systemic circulation and local
Clinical consequences of inflammation
Many clinical manifestations of tumour-associated inflammation contribute to patient outcomes, including clinical symptoms, systemic inflammatory response, necrosis, local inflammatory response, and tumour mutations. Fever is a paraneoplastic effect, thought to be due to increased circulating concentrations of cytokines, such as interleukin 6, TNFα, and interleukin 1. Malignancy is ultimately identified in up to 30% of patients presenting with pyrexia of unknown origin. Fever of more than 38°C,
Non-selective strategies
Harnessing and manipulation of the inflammatory response for therapeutic benefit is an area of intense interest. Broadly, strategies can be divided into those that target systemic inflammation more generally, often via unknown targets, and those that selectively alter specific pathways or components of the immune and inflammatory response within the local tumour microenvironment or systemic circulation (table 2).
Aspirin and non-steroidal anti-inflammatory drugs (NSAIDs), including
Conclusion
The interplay between local and systemic inflammation and tumour progression is complex and includes components of the adaptive, humoral, and innate immune systems. However, such interactions clearly alter the disease course of a wide range of common solid tumours. Although our present knowledge is rudimentary, the potential exists to alter the disease course with currently available, safe, inexpensive, non-selective, anti-inflammatory drugs. With increased understanding of the specific
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