The immune system is one of the most complex, nuanced biological systems that function to keep the human race alive each and every day. It is both specific and broad, lifelong, and short-term, inherited and acquired, all at the same time. While it defends against deadly threats such as bacteria and viruses, defects in the immune system can be just as fatal. The Immune System 101 articles describe how this contradictory system works and will summarize the variety of functions of the immune system, its importance, and its potential failings in six different articles.
6. The Human Immune System 101: The Immune System and Cancer
When cancer cells begin to form in the body, the immune system acts as the main line of defense against tumor formation. Both the adaptive and innate immune systems play crucial roles in controlling tumor growth, however, this is not always enough to prevent cancer cells from proliferating at a rate the immune system cannot control. The immune system recognizes and destroys not only foreign pathogens but also cells that are sick, either with a viral infection or cancerous mutation. Cancer occurs when a healthy cell begins to divide and multiply at an uncontrolled rate to form tumors.
In principle, tumor development can be controlled by cytotoxic innate and adaptive immune cells; however, as the tumor develops from neoplastic tissue to clinically detectable tumors, cancer cells evolve different mechanisms that mimic peripheral immune tolerance in order to avoid a tumoricidal attack (Gonzalez et al., 2018, p. 1).
Figure 1: T Cells (Grey) Attacking a Cancer Cell (Purple). Shutterstock. 2020
How the Immune System Fights Cancer
To understand how the immune system recognizes cancer cells, it is first important to understand how a healthy cell becomes a cancer cell. The cell cycle—in which a cell’s genetic material is replicated and the cell divides into two identical cells—is a highly regulated process to prevent cancer and tumor growth. There are many different checkpoints throughout the cell cycle that require cellular signals to stimulate cell growth, DNA replication, and division (Chow, 2010, p. 1). Proto-oncogenes that encode for these cell cycle regulator proteins can become mutated from environmental factors such as UV light or mistakes in the replication of a cell’s genetic material. When this happens, the proto-oncogene becomes an oncogene: a mutated gene that can cause a healthy cell to become a cancer cell. For example, proteins known as RAS are one of many responsible for signaling a cell to grow and divide when the protein is in its active state. “Problems arise, however, when mutations convert the proto-oncogene to an oncogene, rendering Ras permanently active regardless of the signals the cell receives,” (Chow, 2010, p. 1). In addition to proto-oncogenes which provide the cell with signals to activate the cell cycle, tumor suppressor genes function to restrict the cell cycle at certain checkpoints or activate programmed cell death (apoptosis). A common tumor suppressor, known as the p53 gene, prevents DNA from replicating after the DNA is damaged. When a mutation occurs in the p53 gene, the cell cycle will continue even if DNA damage is present, and when other tumor suppressor genes experience a loss of function mutation, cell division may proceed unchecked (Chow, 2010, p. 1).
Figure 2: Tumor Suppressor Gene Mutations. National Institute of Health- National Human Genome Research Institute. Daphne W. Bell. 2022
It is essential for the immune system to be able to determine which cells are cancer cells and which cells are normal, healthy cells. This can be particularly difficult as a healthy immune system is typically equipped to distinguish between self and non-self-cells, and cancer cells are mutated self-cells. “In this regard, cancer antigens recognized by the human immune system are self or mutated self-molecules,” (Houghton & Guevara-Patiño, 2004, p. 1). It has been found that cancer cells have mutations in self-proteins that, when presented on the MHC molecules, are recognized by immune cells as foreign instead of self. T cells are utilized by a person’s immune system for fighting cancer cells with assistance from dendritic cells and other antigen-presenting cells (APCs); “Naive T cells that have never been activated by antigen are initially triggered by TCR recognition of specific peptide/MHC complexes presented by dendritic cells,” (Houghton & Guevara-Patiño, 2004, p. 2). Cytotoxic T cells, after activation by an APC, function to kill tumor cells through the release of cytotoxic granules in the extracellular space (Cornel et al., 2020, p. 3). In addition to T cells and dendritic cells, natural killer cells also play a key role in tumor destruction. Cancer cells with uncontrolled proliferation produce certain ligands (molecules that bind to receptors) which are recognized by receptors on natural killer cells. For example, the RAE1 ligand produced by cancer cells is recognized by the NKG2D receptor on natural killer cells, along with ligands produced by the RAS pathway and DNA damage (Gonzalez et al., 2018, p. 2). The NKG2D receptor is essential for recognizing cancer cells, and after recognition, natural killer cells destroy cancer cells by releasing cytotoxic perforins, granzymes, and tumor necrosis factor-alpha (TNF-α) (Gonzalez et al., 2018, p. 2).
Figure 3: How T Cells Kill Tumor Cells. Journal of Experimental Medicine. Jill M. Fritz & Michael J. Lenardo. 2019
How Tumors Evade Destruction
While the immune system is highly effective at detecting and destroying cancer cells, tumors are still able to grow in the face of white blood cells. One way that this is accomplished is through loss of antigenicity. When tumor cells present antigens on their surface, the cells alert immune cells that something is wrong and that the cell needs to be destroyed. However, this also allows for the selection of cancer cells that—for one reason or another—do not present these antigens. For example, cancer cells can have mutations that cause a loss of MHC compounds which are necessary for antigen presentation (Beatty & Gladney, 2015).
Tumors which lose MHC expression or acquire defects in antigen presentation may escape immune-mediated elimination by tumor-specific T cells. To this end, downregulation of MHC class I molecules has been found in approximately 20-60% of common solid malignancies including melanoma, lung, breast, renal, prostate, and bladder cancers (Beatty & Gladney, 2015).
Another way that tumor cells can avoid the immune system is through immune suppression. Cancer cells can release anti-inflammatory and immunosuppressive cytokines to suppress the function of cytotoxic T cells and other lymphocytes (Vinay et al., 2015, p. 3). Besides only cytotoxic T cells, cancerous cells can produce vascular endothelial growth factors (VEGF) which both promote tumor growth and inhibit the production of dendritic cells. As dendritic cells are an essential APC that functions to active T cells and other innate and adaptive immune cells, without them, a tumor is able to increase its ability to evade the immune system. Furthermore, similar to how healthy cells exhibit immune tolerance so as to not elicit an immune response, tumor cells are able to develop tolerance over time. “Tumor expression of inhibitory molecules like programmed cell death (PD)-L1/B7H1 has been shown to cause deletion or anergy [lack of reaction by the immune system] on tumor reactive cells,” (Vinay et al., 2015, p. 3). Finally, tumors can evade destruction by immune cells by inducing apoptosis. Certain studies have shown that tumor cells can delete specific cytotoxic T cells through apoptosis, thereby fending off the attack (Vinay et al., 2015, p. 3).
Figure 4: Immune Evasion by Cancer Cells. Cancer Management Research. Marianne Davies. 2014
The immune system works extremely hard to ensure that cancerous cells are detected and killed before tumor proliferation and metastases occur. However, this system is not fail-proof. Just as the immune system is highly tuned to distinguish between cancerous cells and healthy cells, tumor cells are highly skilled in evading the immune system which allows for tumors to proliferate and invade other parts of the body besides their origin point. However, without the immune system, cells with mutations in proto-oncogenes and tumor suppressor genes would survive to proliferate without control whenever these mutations arise.
Beatty, G. L., & Gladney, W. L. (2015, February 15). Immune Escape Mechanisms as a Guide for Cancer Immunotherapy. Clinical Cancer Research, 21(4), 687–692. https://doi.org/10.1158/1078-0432.ccr-14-1860
Chow, A. Y. (2010) Cell Cycle Control by Oncogenes and Tumor Suppressors: Driving the Transformation of Normal Cells into Cancerous Cells. Nature Education 3(9):7 https://www.nature.com/scitable/topicpage/cell-cycle-control-by-oncogenes-and-tumor-14191459/
Cornel, A. M., Mimpen, I. L., & Nierkens, S. (2020, July 2). MHC Class I Downregulation in Cancer: Underlying Mechanisms and Potential Targets for Cancer Immunotherapy. Cancers, 12(7), 1760. https://doi.org/10.3390/cancers12071760
Gonzalez, H., Hagerling, C., & Werb, Z. (2018, October 1). Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes &Amp; Development, 32(19–20), 1267–1284. https://doi.org/10.1101/gad.314617.118
Houghton, A. N., & Guevara-Patiño, J. A. (2004, August 16). Immune recognition of self in immunity against cancer. Journal of Clinical Investigation, 114(4), 468–471. https://doi.org/10.1172/jci22685
Vinay, D. S., Ryan, E. P., Pawelec, G., Talib, W. H., Stagg, J., Elkord, E., Lichtor, T., Decker, W. K., Whelan, R. L., Kumara, H. S., Signori, E., Honoki, K., Georgakilas, A. G., Amin, A., Helferich, W. G., Boosani, C. S., Guha, G., Ciriolo, M. R., Chen, S., . . . Kwon, B. S. (2015, December). Immune evasion in cancer: Mechanistic basis and therapeutic strategies. Seminars in Cancer Biology, 35, S185–S198. https://doi.org/10.1016/j.semcancer.2015.03.004
Cover image: Unknown. How the Immune System Fights Off Threats. Wildpixel/Canva. (2020). [Illustration]. Image retrieved from https://www.todayonline.com/singapore/explainer-how-human-body-fights-infection-and-how-you-can-boost-your-immunity
Figure 1: Unknown. T Cells (Grey) Attacking a Cancer Cell (Purple). Shutterstock. (2020). [Illustration]. Image retrieved from https://blogs.iu.edu/sciu/2020/08/22/cancer-invisibility-cloak/
Figure 2: Bell, D.W. Tumor Suppressor Gene Mutations. National Institute of Health- National Human Genome Research Institute. (2022). [Illustration]. Image retrieved from https://www.genome.gov/genetics-glossary/Tumor-Suppressor-Gene
Figure 3: Fritz, J.M. & Lenardo, M.J. How T Cells Kill Tumor Cells. Journal of Experimental Medicine. (2019). [Illustration]. Image retrieved from https://rupress.org/jem/article-pdf/216/6/1244/1173252/jem_20182395.pdf
Figure 4: Davies, M. Immune Evasion by Cancer Cells. Cancer Management Research. (2014). [Illustration]. Image retrieved from https://www.researchgate.net/figure/mmune-evasion-or-immunosuppressive-strategies-used-by-tumor-cells-Notes-Tumors-use_fig1_260150346