The Immune Balancing Act: Cancer and Autoimmunity
The immune system exists as a spectrum of immune responses from an overactive immune system to an underreactive one. While cancer and autoimmunity sit at opposite ends of the spectrum, treating autoimmunity can increase cancer risk and treating cancer can increase autoimmune disease risk. These diseases and their treatment effects are so intertwined because the same pathways and cells in the immune system are implicated in both disease states.
Immune Cell Dysfunction in Autoimmunity and Cancer
These cells in common include T cells and B cells, where their dysfunction leads to disease. The action of these cells is governed by a complex network of signals that regulate their activation and tolerance to our own cells.
T cells: T cells are the immune cells that attack and kill cells infected with viruses or bacteria. However, during autoimmunity, T cells attack our own cells. In cancer, T cells get “fooled” by the cancer cells because they resemble normal cells. “They are still cells of the individual,” says Davide Mangani, a Principal Investigator studying cancer and immunity at the Institute for Research in Biomedicine, so it makes it difficult for the immune system to distinguish them from non-cancerous cells.
B cells: B cells typically produce antibodies that target viruses and bacteria, which help mark them for destruction. However, in autoimmunity, B cells produce autoantibodies, which are antibodies against our own cells. B cells normally have the ability to present antigens to T cells to activate them so it’s possible that they can present tumor antigen to T cells to instruct them to attack tumor cells.
“In cancer, this activity is something that we would like to see, whereas in autoimmunity, it’s something that we like to block,” says Mangani.
However, in cancer, a type of B cell called regulatory B cells dampens the immune response and secrete factors to inhibit T cells from attacking tumors.
How Do Cancer Treatments Trigger Autoimmune Effects?
In cancer, tumor cells have found ways to evade the host immune system by increasing our body’s tolerance to them. They do this by interfering with immune checkpoints, which normally govern when an immune response should be turned off. Cancer drugs, like immune checkpoint inhibitors, counteract this by blocking these checkpoints so that the immune system can better recognize and destroy tumor cells. Current immune checkpoints being targeted in cancer therapeutics include those that block CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4), PD-1 (programmed death 1), and LAG-3 (lymphocyte activation gene 3) (1, 2).
“The new therapies for cancer try to lower the activation threshold of a T cell. Now these cells are able to attack the tumor cells,” says Mangani. “But, what we also see by lowering this threshold is that you can increase the chance that some T cells start recognizing normal cells.”
This phenomenon is known as immune-related adverse events (irAEs). These irAEs are rare but can affect nearly every organ. While some irAEs are more limited, some are more systemic and dangerous, resulting in widespread inflammation or arthritis that become really debilitating, says Mangani. “If they’re too strong, you need to stop the therapy,” he adds.
However, irAEs are hard to predict. “What’s really difficult about that is that we currently don’t have strategies to identify who might be at risk for these immune-related adverse events and where they’re going to occur,” says Arabella Young, an Assistant Professor in the Department of Pathology and Huntsman Cancer Institute at the University of Utah. In the future, if we can understand why some people respond to immune checkpoint inhibitors alongside patient risk for irAEs, Young thinks that personalized treatments can be tailored to maximize a treatment’s effectiveness against cancer while minimizing irAEs.
Treating cancer while minimizing autoimmune reactions is a balancing act. Evidence finds that:
- Patients who developed irAEs had better treatment outcomes than those who did not (3, 4).
- Corticosteroids, which can be used to treat irAEs, can lower the antitumor immune response during immune checkpoint inhibitor treatment if used too early (5).
“That balance of risk versus benefit is not one that’s very easy for clinicians to delineate at the moment,” says Young.
Autoimmune Therapies Increase Cancer Risk
While immunosuppressive therapies have greatly improved the quality of life for people with autoimmune diseases, immunosuppressants and biologics can increase cancer risk by weakening immune surveillance. This can make the body less able to find and destroy cancer cells or fight off viral infections like human papillomavirus or Epstein-Barr virus that increase the risk of developing cancer (6). The general recommendation for those on immunosuppressive therapy has been to monitor for cancer development by routine and early screening.
However, the link between the immunosuppressive effects of these drugs and cancer is unclear, as having an immune-related disease itself increases the risk of cancer (6, 7).
For example, a study in patients with ocular inflammatory disease found no links between overall or site-specific cancer and the use of multiple immunosuppressive drugs (6). Another study found that short-term use of immunosuppressive drugs was not linked to cancer (8).
Yet, other studies find the opposite. Treatment with TNF inhibitors is linked to an elevated risk for skin cancer and lymphomas (9), so patients on these drugs should look out for unusual changes in the skin. However, the risk of most other cancers wasn’t elevated with TNF inhibitor treatment (9). Treatment with methotrexate was linked to an elevated risk for basal cell carcinoma and squamous cell carcinoma (10). However, the study also acknowledges the possibility of surveillance bias – those on methotrexate are more likely to undergo skin examinations compared to those who aren’t.
A Balancing Act
The connectedness between autoimmunity and cancer highlights how the immune system can be swayed towards overactivity or underactivity. “It’s a balancing act,” said Young. With continued research, it’s possible that scientists will understand more about keeping undesirable immune responses in check when treating autoimmunity or cancer. Personalized treatment can also help avoid adverse outcomes by tailoring treatment to the individual.
About the Author
A microbiologist turned freelance science writer who works with life science companies, nonprofits, and academic institutions on anything from news stories, explainer articles, and content marketing. She shares the wonderful world of microbes on her blog The Microbial Menagerie.
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