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Essential Principles of Immunology

Differentiating self from nonself is a hallmark of the immune response

The immune system is a network of tissues, cells, and signaling molecules that work to protect the body by recognizing and attacking foreign cells, while seeking to minimize the damage to healthy cells.1,2 This ability to differentiate self (the body’s own normal cells) from nonself (abnormal/foreign cells) is a hallmark of the immune response.2,3

The capacity of the immune system to recognize self-antigens and accept the presence of normal cells is known as self-tolerance.2 When self-tolerance fails, it can result in autoimmunity, whereby the immune system may fail to discriminate self from nonself and attack normal cells.4

Co-inhibitory signaling pathway expressed in a self antigen diagram and a co-stimulatory signaling pathway expressed in a nonself antigen diagram

To prevent autoimmunity, immune cells learn to overlook self-antigens, both during their maturation (central tolerance) and as they circulate in peripheral tissue (peripheral tolerance).2 Most self-reactive T cells are eliminated early in their development; however, peripheral tolerance exists to prevent recognition of self-antigens that may not have been encountered during maturation. Immune checkpoint pathway interaction is one mechanism of peripheral tolerance.2,5

Both innate and adaptive immune systems can differentiate self from nonself

Innate immune response is rapid, while adaptive immune response is not as immediate but can produce a durable response through the development of memory cells, including memory
T cells
.1,8 Chronic exposure to a nonself antigen can promote the accumulation of memory T cells.8 Innate and adaptive immunity are activated through distinct and often complementary mechanisms that deploy different effector cells to attack and destroy abnormal/foreign cells such as cancer.1

Memory response expressed in a chart comparing innate immune response to adaptive immune response over time

Innate immunity, the body’s first line of defense, is non-specific, short-lived, 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 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

Diagram of NK cell recognition and activation leading to tumor cell death

Upon recognition of a tumor cell through engagement of an activating receptor, NK cells proliferate and rapidly kill their target.3,4 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.5-7

Adaptive immunity is antigen-dependent, antigen-specific, and able to produce a durable response.1 In cancer, tumor antigens such as those released by tumor-cell death are derived from mutated or modified self-proteins.12 Tumors that have more somatic mutations—known as a higher mutational burden—may have the potential to generate a larger number of neoantigens.13 When more tumor antigens are present in the tumor microenvironment, there may be a greater opportunity to stimulate T-cell activity.13,14

Antigen-presenting cells (APCs) are central messengers between innate and adaptive immunity

Tumor-cell death allows the release of certain molecules, such as adenosine triphosphate (ATP) and tumor DNA, that can cause the activation of APCs, including dendritic cells.1,2 APCs act as messengers between the innate and adaptive immune response.3

Diagram of inflammasome and intracellular DNA-sensor protein activity inside of a Dendritic cell

Inflammatory signals such as ATP can trigger the formation of an inflammasome within the APC.1,2 Inflammasomes are protein complexes that initiate an inflammatory immune response, recruitment, and response of innate immune cells by converting proinflammatory cytokines from a dormant to an active state.4 Once activated, these cytokines are released by APCs to increase the antitumor activity of NK cells and T cells.1,4,5

T cells can destroy tumor cells and provide long-term immunity

Antigen recognition later causes activated T cells to migrate to and infiltrate the tumor site. Following infiltration into the tumor, cytotoxic T cells release secreted factors capable of promoting tumor-cell death.3 Early evidence suggests that a higher mutational burden may be associated with an increased likelihood of greater infiltration of cytotoxic T cells.10

Upon resolution of the immune attack, cytotoxic T cells either die or differentiate into memory T cells that persist long term.11 Memory T cells can re-recognize the antigen, providing the potential for a subsequent immune response.3,12

To identify and eliminate tumor cells, cytotoxic and memory T cells must be able to scan peripheral tissues in search of their unique activating antigen.1,2 To make this possible, activated T cells upregulate factors that enable them to recognize threats and migrate through blood vessel walls and into affected tissues.3,4 T-cell migration occurs across non-lymphoid tissues, with documented trafficking to particularly selective organs such as the eye and brain.5-11

Diagram of an activated memory t cell migrating throughout the body to recognize tumor antigens

Though the brain was once thought to be “immune privileged,” data suggest that the blood-brain barrier can be “leaky,” allowing for the movement of T cells and other immune molecules. This mobility enables activated cytotoxic T cells to patrol for antigens and infiltrate tumors in the brain.5,12 After the activated cytotoxic T-cell population diminishes, memory T cells remain capable of trafficking to surrounding tissues in the event of antigen reoccurence.6

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REFERENCES–Revealing the potential of I-O

1. Warrington R, Watson W, Kim HL, Antonetti FR. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011. doi:10.1186/1710-1492-7-S1-S1. 2. Van Parijs L, Abbas AK. Homeostasis and self-tolerance in the immune system: turning lymphocytes off. Science. 1998;280(5361):243-248. 3. Mapara MY, Sykes M. Tolerance and cancer: mechanisms of tumor evasion and strategies for breaking tolerance. J Clin Oncol. 2004;22(6):1136-1151. 4. Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Rev Immunol. 2004;22:531-562. 5. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer.
2012;12(4):252-264 6. Janeway Jr CA, Travers P, Walport M, Shlomchik MJ. Immunobiology: the immune system in health and disease. 5th ed. New York, NY: Garland Publishing; 2001. 7. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348(6230):69-74. 8. Nikolich-Žugich J. Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat Rev Immunol. 2008;8(7):512-522.

REFERENCES–NK cells are the main effectors of the innate immune system

1. Warrington R, Watson W, Kim HL, Antonetti FR. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011. 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. 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. 5. 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. 6. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol. 2008;9(5):503-510. 7. 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. 8. 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. 9. 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. 10. 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. 11. Smyth MJ, Cretney E, Kelly JM, et al. Activation of NK cell cytotoxicity. Mol Immunol. 2005;42(4):501-510. 12. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348(6230):69-74. 13. Liontos M, Anastasiou I, Bamias A, Dimopoulos M-A. DNA damage, tumor mutational load and their impact on immune responses against cancer. Ann Transl Med. 2016. doi:10.21037/atm.2016.07.11. 14. Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27(8):1492-1504. 15. Mondino A, Khoruts A, Jenkins MK. The anatomy of T-cell activation and tolerance. Proc Natl Acad Sci
U S A.
1996;93(6):2245-2252. 16. Krummel MF, Bartumeus F, Gérard A. T cell migration, search strategies and mechanisms. Nat Rev Immunol. 2016;16(3):193-201. 17. Lau LL, Jamieson BD, Somasundaram T, Ahmed R. Cytotoxic T-cell memory without antigen. Nature. 1994;369(6482):648-652.

REFERENCES–APCs are central messengers between innate and adaptive immunity

1. 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. 2. 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. 3. Warrington R, Watson W, Kim HL, Antonetti FR. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011. doi:10.1186/1710-1492-7-S1-S1. 4. He Y, Hara H, Núñez G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem Sci. 2016;41(12):1012-1021. 5. 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. 6. 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. 7. Corrales L, McWhirter SM, Dubensky Jr TW, Gajewski TF. The host STING pathway at the interface of cancer and immunity. J Clin Invest. 2016;126(7):2404-2411. 8. Janeway Jr CA, Travers P, Walport M, Shlomchik MJ. Immunobiology: the immune system in health and disease. 5th ed. New York, NY: Garland Publishing; 2001. 9. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264. 10. Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27(8):1492-1504. 11. Masopust D, Schenkel JM. The integration of T cell migration, differentiation and function. Nat Rev Immunol. 2013;13(5):309-320. 12. Lau LL, Jamieson BD, Somasundaram T, Ahmed R. Cytotoxic T-cell memory without antigen. Nature. 1994;369(6482):648-652.

REFERENCES–Activated and memory T cells can migrate throughout the body and recognize tumor antigens

1. Krummel MF, Bartumeus F, Gérard A. T cell migration, search strategies and mechanisms. Nat Rev Immunol. 2016;16(3):193-201. 2. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264. 3. Slaney CY, Kershaw MH, Darcy PK. Trafficking of T cells into tumors. Cancer Res. 2014;74(24):7168-7174. 4. Ferguson AR, Engelhard VH. CD8 T cells activated in distinct lymphoid organs differentially express adhesion proteins and coexpress multiple chemokine receptors. J Immunol. 2010;184(8):4079-4086. 5. Masopust D, Vezys V, Usherwood EJ, et al. Activated primary and memory CD8 T cells migrate to nonlymphoid tissues regardless of site of activation or tissue of origin. J Immunol. 2004;172(8):4875-4882. 6. Woodland DL, Kohlmeier JE. Migration, maintenance and recall of memory T cells in peripheral tissues. Nat Rev Immunol. 2009;9(3):153-161. 7. Hirata T, Furie BC, Furie B. P-, E-, and L-selectin mediate migration of activated CD8+ T lymphocytes into inflamed skin. J Immunol. 2002;169(8):4307-4313. 8. Wekerle H, Sun D. Fragile privileges: autoimmunity in brain and eye. Acta Pharmacol Sin. 2010;31(9):1141-1148. 9. Agace WW. Tissue-tropic effector T cells: generation and targeting opportunities. Nat Rev Immunol. 2006;6(9):682-692. 10. Walch JM, Zeng Q, Li Q, et al. Cognate antigen directs CD8+ T cell migration to vascularized transplants. J Clin Invest. 2013;123(6):2663-2671. 11. Dace DS, Chen PW, Niederkorn JY. CD8+ T cells circumvent immune privilege in the eye and mediate intraocular tumor rejection by a TNF-α-dependent mechanism. J Immunol. 2007;178(10):6115-6122. 12. Masson F, Calzascia T, Di Berardino-Besson W, de Tribolet N, Dietrich P-Y, Walker PR. Brain microenvironment promotes the final functional maturation of tumor-specific effector CD8+ T cells. J Immunol. 2007;179(2):845-853.