Innate Immunity and Cancer Pathophysiology

Abstract

Chronic inflammation increases the risk of several cancers, including gastric, colon, and hepatic cancers. Conversely, tumors, similar to tissue injury, trigger an inflammatory response coordinated by the innate immune system. Cellular and molecular mediators of inflammation modulate tumor growth directly and by influencing the adaptive immune response. Depending on the balance of immune cell types and signals within the tumor microenvironment, inflammation can support or restrain the tumor. Adding to the complexity, research from the past two decades has revealed that innate immune cells are highly heterogeneous and plastic, with variable phenotypes depending on tumor type, stage, and treatment. The field is now on the cusp of being able to harness this wealth of data to (a) classify tumors on the basis of their immune makeup, with implications for prognosis, treatment choice, and clinical outcome, and (b) design therapeutic strategies that activate antitumor immune responses by targeting innate immune cells.

Keywords: cancer immunology; immuno-oncology; inflammation; innate immunity; plasticity; tumor microenvironment.

Fig. 1.. Plasticity of the innate immune system

The components of the innate immune system are not inherently tumor-supportive or tumor-opposing. Rather, cells of the innate immune system are highly plastic and their phenotype and activity depend on the balance of signals within the tumor. (a) The anti-tumorigenic functions of the innate immune system include 1) antigen presentation and activation of the adaptive response, 2) direct killing of cancer cells, and 3) amplification of the anti-tumor immune response through cytokine secretion. (b) During tumor progression signals from tumor cells and other cells in the microenvironment can polarize innate immune cells towards supporting the tumor, e.g., through 4) angiogenesis, 7) ECM remodeling, 5, 6, 8) immunosuppression, and 9, 10) pro-metastatic activities. Thus, because of plasticity, the innate immune system has tumor-promoting potential. However, plasticity also affords us the opportunity to therapeutically reprogram the innate immune system to fight the tumor. Abbreviations: DC, dendritic cell; ECM, extracellular matrix; IDO, indoleamine 2,3-dioxygenase; IL, interleukin; ILC, innate lymphoid cell; MDSC, myeloid-derived suppressor cell; NET, neutrophil extracellular trap; NK, natural killer; NKT, natural killer T; NO, nitric oxide; ROS, reactive oxygen species; TAM, tumor-associated macrophage; TGF, transforming growth factor; VEGF, vascular endothelial growth factor.

Fig. 2.. Aberrant wound healing response, fibrosis, and cancer

Partly owing to the activation of the innate immune system, features of the tumor microenvironment resemble an aberrant wound healing response. Wound healing consists of overlapping phases (left). Injury of adult tissue results in local hemorrhage, immediately followed by clotting. A temporary matrix of fibrin is deposited locally, which serves as a scaffold for migrating immune cells, epithelial cells, fibroblasts, and endothelial cells. During wound healing, neutrophils and macrophages kill bacteria, degrade the fibrin clot, and remove cellular debris. Neutrophils also secrete mediators such as TNF-α, IL-1β, and IL-6, amplifying the innate response. Macrophages produce VEGF and other growth factors, such as TGF-β, that stimulate the next phase: migration and proliferation of cells within the wound. In this phase blood supply is restored, new connective tissue is produced, and the wound re-epithelializes. Lastly, during the repair phase, the extracellular matrix is remodeled and new blood vessels are culled. Failure to clear the rich inflammatory infiltrate results in chronic inflammation (right). The persistence of inflammatory cells results in the accumulation of toxic compounds such as reactive oxygen and nitrogen species, as well as cytokines, which support tumor initiation and progression and sustain myofibroblast activation and fibrosis. Inflammation, fibrosis, and cancer are tightly linked in a vicious cycle, in which they can each trigger and aggravate the other. Abbreviations: ECM, extracellular matrix; EMT, epithelial–mesenchymal transition; IL, interleukin; RNS, reactive nitrogen species; ROS, reactive oxygen species; TGF, transforming growth factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.

Fig. 3.. Interactions between cancer and the innate immune system

Cellular and molecular components of innate immunity interact with cancer cells through a variety of mechanisms that can support or restrain tumor growth. (a) By virtue of the high degree of plasticity of innate immune cells, cytokines secreted in the tumor microenvironment can polarize innate immune cells toward tumor-supportive phenotypes. (b) Necrotic cells release DAMPs, endogenous “danger signals” recognized by pattern recognition receptors (PRRs), e.g., Toll-like receptors (TLRs), on innate immune cells. DAMP sensing increases phagocytosis of the necrotic debris and amplifies the inflammatory response, leading to activation of the adaptive immune response. Opposite mechanisms also exist. For example, the binding of CD47 to SIRPα helps cancer cells escape phagocytosis, by transmitting a “don’t eat me” signal. (c) Innate lymphoid cells (ILCs and NK cells) and unconventional T lymphocytes (γδ T cells and NKT cells) can directly eliminate tumor cells by releasing cytotoxic granules or engaging death receptors. In NK cells, this cytotoxic activity is regulated by cancer cell ligands that bind either activating or inhibitory surface receptors. Unconventional T lymphocytes recognize cancer cells through their TCR. The γδ TCR allows for non-MHC-restricted recognition of e.g., phosphoantigens. The invariant or semi-invariant TCR on NKT cells binds lipid antigens presented on the non-polymorphic MHC-I-like molecule CD1d. (d) The complement system can mediate tumor cell lysis and phagocytosis by immune cells, e.g., by binding anti-cancer antibodies on the surface of cancer cells. By contrast, cleavage products of complement activation (C3a and C5a) can support tumor growth, either by directly affecting cancer cells or by recruiting immunosuppressive cells. Abbreviations: DAMP, danger-associated molecular pattern; G-CSF, granulocyte colony–stimulating factor; HSP, heat shock protein; IL, interleukin; ILC, innate lymphoid cell; M-MDSC, monocytic myeloid-derived suppressor cell; M-CSF, macrophage colony stimulating factor; MHC, major histocompatibility complex; NK, natural killer; NKT, natural killer T; PGE₂, prostaglandin E2; PMN-MDSC, polymorphonuclear myeloid-derived suppressor cell; PRR, pattern recognition receptor; SIRPα, signal-regulatory protein α; TAM, tumor-associated macrophage; TAN, tumor-associated neutrophil; TCR, T cell receptor; TLR, Toll-like receptor.