Immunity , inflammation , and cancer : an eternal fight between good and evil

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 B lymphocytes, further amplify the initial inflammatory response. Thus, type 1 helper T cells (Th1 cells) activate macrophages both through cell-to-cell contact and IFN-γ secretion (8), Th2 cells activate eosinophils through cytokine release, and B cells secrete antibodies that activate the complement cascade — as well as phagocytes, NK cells, and mast cells — through Fc receptors (7, 9–12). However, certain adaptive immune cells, especially Tregs, can turn off the inflammatory response (13). The major driving forces that contribute to evolution of the immune system are infectious organisms capable of eliciting direct damage to the host. Yet, despite its sophistication, the immune system can cause substantial collateral damage (immunopathology) when over-activated or not properly terminated. To minimize immunopathology and maximize host defense, innate and adaptive immune cells are equipped with negative regulatory mechanisms (14–18). In fact, maximal immunity is achieved only when innate and adaptive immune cells act in concert and harmony, which also depends on negative control or immunosuppressive mechanisms. For instance, during chronic viral infections, viruses are held at bay while avoiding immunopathological damage by immune checkpoints that prevent an overzealous antiviral response (19). These evolutionarily conserved controls may also be involved in T cell tolerization during cancer-associated chronic inflammation (20, 21), although the underlying mechanisms remain obscure (22–24). In this review, we will discuss how innate and adaptive immune cells control tumor progression and the response to therapy, and we will try to avoid extensive discussion of the entire inflammation and cancer field, which has been reviewed elsewhere (20, 25, 26).