Revealing the Potential of the Immune System in Cancer
The immune system can recognize and eliminate tumor cells
Innate and adaptive immunity act as complementary networks of self-defense against foreign threats, including pathogens and cancer.1 An essential feature of the immune system is its ability to recognize foreign threats (nonself) as distinct from normal cells (self).2-4 Although they originate from normal cells, tumor cells have mutated and can be recognized as nonself by both the innate and adaptive immune systems.5.6
The innate immune response is the body’s first line of defense against pathogens and cancer.1,5,7 It is rapid and antigen-independent.1 It is constantly on alert and can rapidly identify and attack tumor cells. The speed and scope of its response are not limited by antigen specificity, but they are regulated to protect normal cells. The innate immune response recognizes activating and inhibitory signals from target cells to distinguish self from nonself. This distinction allows for the elimination of tumor cells, while sparing normal cells.8-10
Natural killer (NK) cells are the main effector cells of the innate immune system.11 Through engagement of an activating receptor, NK cells recognize tumor cells as nonself and target them for destruction.9
The adaptive immune response is antigen-specific and able to produce a durable response.1,7 Although not immediate, once the adaptive immune response is activated, it can be sustained through an immune memory response.12 Cytotoxic T cells are effector cells of the adaptive immune system.1
Antigen-presenting cells (APCs), such as dendritic cells, are innate immune cells that can act as central messengers between the innate and adaptive immune responses.1 Tumor cell death, which can be initiated by the innate immune system, can release signaling molecules, such as DNA, adenosine triphosphate (ATP), and proteins.13-16 These factors may cause APCs to initiate an adaptive immune response.13,16
DNA or ATP released by dying tumor cells stimulates APCs to produce proinflammatory cytokines. These cytokines activate T cells and promote tumor inflammation.16,17 One mechanism by which APCs produce these cytokines is the formation of a protein complex known as the inflammasome.18,19 Inflammasome-activated cytokines can support antitumor function and survival in activated T cells involved in the adaptive immune response.16,18
Proteins released by dying tumor cells can be processed by APCs into tumor antigens.20,21 APCs present these antigens to T cells, priming them to recognize tumor cells.1,21
Neoantigens are a class of tumor antigen that are derived from the unique mutations in tumor DNA that differentiate tumors from normal tissue.6 Neoantigens are thus unique to the tumor and recognizable as nonself by the immune system.6,22 The collective number of somatic (acquired) mutations within the tumor genome is known as the tumor mutational burden (TMB).23,24 Some tumors have a higher mutational burden than others.25,26 Infiltration of cytotoxic T cells into the tumor microenvironment may be closely linked to a high tumor mutational burden—the more neoantigens produced, the greater the potential for T-cell activation and infiltration.27,28
The key stages of the antitumor immune response
In both the innate and adaptive immune responses, as described above, immune cells have the potential to recognize and eliminate abnormal cells such as tumor cells.
There are three principal stages in this process:
- Presentation: the innate immune system rapidly identifies and attacks tumor cells. The resulting tumor cell death releases tumor antigens, which can activate the cytotoxic T cells of the adaptive immune system14,29
- Infiltration: tumor antigens and other factors attract immune cells to the tumor site, where they invade and attack29
- Elimination: activated cytotoxic T cells recognize tumor cells as the source of the antigen and target them for elimination29
The antitumor activity of NK and cytotoxic T cells is regulated through a network of activating and inhibitory signaling pathways.30,31 Activating pathways trigger an immune response. Inhibitory pathways, such as immune checkpoint pathways, provide a natural counterbalance to immune activation. This balance between activating and inhibitory pathways normally enables the immune system to attack tumor cells, while sparing healthy cells.31
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- Lau LL, Jamieson BD, Somasundaram T, et al. Cytotoxic T-cell memory without antigen. Nature. 1994;369(6482):648-652.
- 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.
- 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.
- Zhang Q, Zhu B, Li Y. Resolution of cancer-promoting inflammation: a new approach for anticancer therapy. Front Immunol. 2017;8:71. doi:10.3389/fimmu.2017.00071.
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- 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.
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- Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9(1):34. doi:10.1186/s13073-017-0424-2.
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