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Cancer development and its response to therapy are strongly influenced by innate and adaptive immunity, which either promote or attenuate tumorigenesis and can have opposing effects on therapeutic outcome. Chronic inflammation promotes tumor development, progression, and metastatic dissemination, as well as treatment resistance. However, cancer development and malignant progression are also associated with accumulation of genetic alterations and loss of normal regulatory processes, which cause expression of tumor-specific antigens and tumor-associated antigens (TAAs) that can activate antitumor immune responses. Although signals that trigger acute inflammatory reactions often stimulate dendritic cell maturation and antigen presentation, chronic inflammation can be immunosuppressive. This antagonism between inflammation and immunity also affects the outcome of cancer treatment and needs to be considered when designing new therapeutic approaches.
Introduction
Inflammation has been recognized since the beginning of recorded medical knowledge (1-3). It is a part of a complex biological response to cellular damage caused either by sterile injury (cell death) or infection, in which the immune system attempts to eliminate or neutralize injurious stimuli and initiates healing and regenerative processes. For example, IL-6, a key tumor-promoting inflammatory cytokine produced by innate immune cells, activates at least three regenerationpromoting transcription factors - YAP, Notch, and STAT3 - which are also involved in stem cell activation (4). It is likely that all tumorpromoting inflammation, whether it precedes or follows tumor development, is part of the normal response to injury and infection that has been usurped by cancer cells to their own advantage.
Inflammation is classically viewed as a feature of innate immunity, which differs from adaptive immunity by the receptors mediating its activation and its rapid onset. Innate immunity is also more evolutionarily ancient than adaptive immunity and is triggered by foreign microbial and viral structures, known as pathogen-associated molecular patterns (PAMPs), or normal cellular constituents released upon injury and cell death, known as damage-associated molecular patterns (DAMPs). Both PAMPs and DAMPs are recognized by pattern-recognition receptors (PRRs), many of which belong to the TLR family (5, 6). Once activated, innate immunity results in upregulation of MHC class I and II and costimulatory molecules, as well as numerous inflammatory chemokines and cytokines that attract and prime T cells for activation through diverse antigen receptors (7). Activated adaptive immune cells, including T and...