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Innate Immunity: Non-specific Defenses

The innate immune response is rapid and antigen-independent

Innate immunity, the body’s first line of defense, is non-specific and activates independently of antigens, allowing for the rapid identification and elimination of foreign threats.1 Numerous cell types are involved with the innate immune response, including macrophages, neutrophils, dendritic cells, mast cells, basophils, eosinophils, natural killer (NK) cells, and lymphocytes (T cells).1 The primary effector cells of the innate immune response, NK cells, continually scan the body for abnormal cells to attack.1-3

NK cells do not rely on antigens to identify nonself invaders.1 Instead, NK cells express receptors that interact with activating and inhibitory signals from normal and abnormal cells. The balance of these signals determines NK-cell behavior.4 By engaging inhibitory receptors on NK cells, normal cells are able to identify themselves as self and protect against immune attack.5 In contrast, tumor cells express ligands that are not typical of normal cells.2,6 When the activating signals of tumor ligands prevail, they stimulate NK-cell antitumor immunity.5,7

NK cells are part of the first line of defense against cancer

Upon recognition of a tumor cell through engagement of an activating receptor, NK cells proliferate and rapidly kill their target.3,8 Following tumor cell death, the NK cells move on in search of other targets.3 In death, tumor cells can release tumor antigens and other factors.9-11

APCs act as primary messengers between innate and adaptive immunity

Tumor cell death allows the release of factors, such as adenosine triphosphate (ATP) and tumor DNA, that can cause the activation of APCs, including dendritic cells.11,12 APCs act as messengers between the innate and adaptive immune response.1

Inflammatory signals such as ATP can trigger the formation of an inflammasome within the APC.11,12 Inflammasomes are protein complexes that initiate an inflammatory immune response by converting proinflammatory cytokines from a dormant to an active state.13 Once activated, these cytokines are released by APCs to increase the antitumor activity of NK and T cells.12-14

Tumor DNA can be detected by sensors within the APC.15 These sensors stimulate the APC to engulf proteins released during tumor cell death and process them into antigens.11,16,17 One of the primary functions of APCs is to present these antigens to inactive T cells.17 The first presentation of an antigen to an inactive T cell leads to its activation and proliferation. This process, known as T-cell priming, initiates the adaptive immune response.17


1. Warrington R, Watson W, Kim HL, Antonetti FR. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011;7(suppl 1):S1-S8. doi:10.1186/1710-1492-7-S1-S1. 2. Cerwenka A, Bakker ABH, McClanahan T, et al. Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor in mice. Immunity. 2000;12(6):721-727. 3. Vanherberghen B, Olofsson PE, Forslund E, et al. Classification of human natural killer cells based on migration behavior and cytotoxic response. Blood. 2013;121(8):1326-1334. 4. Bryceson YT, Ljunggren H-G, Long EO. Minimal requirement for induction of natural cytotoxicity and intersection of activation signals by inhibitory receptors. Blood. 2009;114(13):2657-2666. 5. Campbell KS, Purdy AK. Structure/function of human killer cell immunoglobulin-like receptors: lessons from polymorphisms, evolution, crystal structures and mutations. Immunology. 2011;132(3):315-325. 6. Diefenbach A, Jamieson AM, Liu SD, Shastri N, Raulet DH. Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages. Nat Immunol. 2000;1(2):119-126. 7. Smyth MJ, Cretney E, Kelly JM, et al. Activation of NK cell cytotoxicity. Mol Immunol. 2005;42(4):501-510.
8. André P, Castriconi R, Espéli M, et al. Comparative analysis of human NK cell activation induced by NKG2D and natural cytotoxicity receptors. Eur J Immunol. 2004;34(4):961-971. 9. Liu C, Lou Y, Lizée G, et al. Plasmacytoid dendritic cells induce NK cell–dependent, tumor antigen–specific T cell cross-priming and tumor regression in mice. J Clin Invest. 2008;118(3):1165-1175. 10. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol. 2008;9(5):503-510. 11. Woo S-R, Fuertes MB, Corrales L, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity. 2014;41(5):830-842. 12. Ghiringhelli F, Apetoh L, Tesniere A, et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors. Nat Med. 2009;15(10):1170-1178. 13. He Y, Hara H, Núñez G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem Sci. 2016;41(12):1012-1021. 14. Dupaul-Chicoine J, Arabzadeh A, Dagenais M, et al. The Nlrp3 inflammasome suppresses colorectal cancer metastatic growth in the liver by promoting natural killer cell tumoricidal activity. Immunity. 2015;43(4):751-763. 15. Corrales L, Gajewski TF. Molecular pathways: targeting the stimulator of interferon genes (STING) in the Immunotherapy of Cancer. Clin Cancer Res. 2015;21(21):4774-4779. 16. Corrales L, McWhirter SM, Dubensky TW Jr, Gajewski TF. The host STING pathway at the interface of cancer and immunity. J Clin Invest. 2016;126(7):2404-2411. 17. Janeway CA Jr, Travers P, Walport M, Shlomchik MJ. Immunobiology. 5th ed. Garland Science: New York, NY: 2001.

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