Hidden in Plain Sight: Cancer's Evasion of Immune Detection
Immunotherapy Reprograms the Immune System to Fight Cancer
If your immune system is so powerful, then why does it so often fail to detect cancer?
Most of us think of the immune system as a protective force, like a SWAT team, constantly working to protect us from harmful invaders like bacteria, viruses, and other threats. It’s incredibly good at recognizing and attacking things that could cause harm and don’t belong in the body. But cancer cells are different and sneaky; they actually originate from our own bodies and evolve tactics to evade immune detection, essentially cloaking themselves from attack.
In this article, we’ll break down how cancer hides, why it matters for treatment, and how scientists are learning to expose it. The answer to why the immune system doesn’t always fight cancer lies in the origin of cancer and the way that our immune cells have evolved to tolerate (not respond to) the cells and tissues in our own bodies. Let’s jump in!
Immune Cells Undergo Rigorous Testing to ‘Tolerate’ Self
Our immune cells are tested during development—before they are released into the bloodstream and the body—to ensure only those cells that do not identify cells and tissues in our own bodies as a target survive. Those that do recognize—and have the ability to attack—cells within our own body are destroyed. This destruction is meant to eliminate immune cells that could, in theory, spark an autoimmune attack.
More specifically, it is the B cells and T cells of the immune system that are tested because these cells have individual specificity. Like a snowflake, each B cell and each T cell are slightly different and recognize a different target. The target of one T cell could be a tiny piece of the spike protein on the surface of SARS-CoV-2 (the virus that causes COVID-19) while the target of a different T cell could be a tiny piece of hemagglutinin (the ‘H’) on the surface of the influenza virus. No matter the target, only B cells and T cells that have specificity for something that is not part of the body or ‘self’ should be released into the body.
The Immune System’s Dilemma: Cancer is ‘Self’
Cancer presents a unique challenge to the immune system. Unlike pathogens, which are clearly foreign, cancer cells originate from the body's own “self” cells, undergoing changes that allow them to grow uncontrollably. Although cancer cells are abnormal and dangerous, they look very similar to normal, healthy cells, making it hard for the immune system to tell the difference. In this article, we’ll explore how cancer hides in plain sight and the innovative strategies that scientists are exploring to help the immune system recognize and destroy it.
How Cancer Pulls It Off - Core Strategies
Turning Off the Alarms
Cancer cells are essentially normal cells that—for a variety of reasons—are growing out of control. You can think of cancer cells as cars that have stopped using the brakes, are pushing hard on the gas pedal and are completely out of control. As a result of this uncontrolled growth, some cancer cells stop producing molecules (called major histocompatibility proteins) that act like tiny flags on their surface that would normally alert T cells that there is a problem. This mechanism is similar to turning off a home security system. By reducing or eliminating the display of these molecules, cancer cells avoid triggering an immune response. In a healthy immune system, T cells would usually recognize these flags as signals of danger and attack the abnormal cells. Without these markers, cancer cells can hide in plain sight, making it much more difficult for the immune system to detect and destroy them.
Creating a ‘Bad Vibe’ Immune-Suppressive Environment
Cancer cells secrete substances that create an environment around themselves that suppresses immune responses and makes it harder for immune cells to do their job. It's like a huge crowd of people arriving at an airport security checkpoint at the same time that luggage scanning machines break; the movement of people through the checkpoint slows to a crawl. A similar phenomena can happen with cancer. Cancer often recruits T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs) that create an immune-suppressive microenvironment. These cells secrete anti-inflammatory cytokines that play a role in preventing the immune system from effectively targeting and destroying cancer cells. In essence, the cancer cells confuse the immune system by inviting the wrong cells into the tumor microenvironment, which further hampers the body’s natural defenses.
Blocking Access or Infiltration: The Tumor Fortress Defense
The tumor microenvironment (TME) is a complex ecosystem that surrounds and supports a tumor. It can be in the form of a "fortress," employing a combination of physical and biochemical barriers that defend it from immune surveillance. These barriers not only exclude immune cells from the tumor but can also suppress the effectiveness of therapies that are immune-activation based. When outside forces penetrate the fortress, the inside defenses, such as the immune evasion mechanisms, step in and protect the tumor.
Cancer consists of tumors that grow uncontrollably, using the microenvironment to enhance their growth and spread, leading to the formation of secondary tumors. Tumors often express extracellular matrix (ECM) proteins or stromal cells that physically block immune cell traffic, while also secreting immunosuppressive cytokines like TGF-β to change immune cell behavior. Additionally, the abnormal structure of tumor blood vessels reduces perfusion, preventing the delivery of immune cells and therapeutic agents. We'll dive deeper into the complexities of the TME and its impact on immune evasion in an upcoming article.
Disabling the Immune Brakes
Many cells in our body have molecules on their surface—called checkpoint molecules—that exist as brakes to stop T cells from mistakenly attacking self cells. It’s a built-in safety mechanism to prevent autoimmunity.
But in cancer, these brakes work against us by telling T cells to back off and leave the cancer cells alone. Through years of research, scientists have discovered this cancer trick, and have developed a type of immunotherapy called immune checkpoint inhibitors to block the brakes. Immune checkpoint inhibitors are proteins (antibodies to be precise) that bind to the checkpoint molecules and hide the brake so that any T cells that recognize and target cancer cells are allowed to stay ‘on’ and attack the cancer.
One example where immune checkpoint inhibitors have been completely game changing is melanoma. By blocking checkpoint molecules like PD-1 and CTLA-4, which normally act as brakes on immune responses, these immunotherapies allow T cells to stay active and fight cancer more effectively. This approach has significantly improved survival rates in patients with advanced melanoma, offering long-term remission for patients who previously had very limited options and often succumbed to disease.
Why This Matters
Understanding how cancer cells avoid immune detection is key to explaining uncontrolled tumor growth and immunotherapy failure. Cancer cells destabilize the body's own protective immune mechanisms to escape immune surveillance and avoid elimination, thereby leading to uncontrolled tumor growth. This process is especially undesirable in cancer treatment, since the immune system, which is usually adept at detecting and recognizing foreign intruders, is caught off-guard by these evasive strategies.
In our daily life, immune evasion explains why certain patients, despite having access to therapies like checkpoint inhibitors, don't experience substantial benefits. However, if the tumor microenvironment has already established effective immune evasion mechanisms, these treatments may not be enough.
However, by understanding the mechanisms behind immune evasion, scientists and clinicians are developing more effective cancer therapies. Combination therapy that strikes several immune targets, along with the use of checkpoint inhibitors with other drugs, is showing promise in bypassing these roadblocks. Furthermore, ongoing research is advancing personalized medicine, where new treatments are tailored to the specific tumor type of each patient to enhance their chances of success.
The Science Strikes Back
Researchers are fighting back against immune evasion with innovative strategies designed to outsmart the tumor’s defenses. Checkpoint inhibitors, which block the pathways tumors use to suppress immune activity, have already shown promise, but scientists are taking it a step further.
Chimeric antigen receptor (CAR) T cell therapy engineers a patient’s own immune T cells to recognize specific markers found only on cancer cells. Adding this engineered receptor to the patient’s own T cells redirects their specificity and gives the body a powerful new system to target and destroy the cancer. Cancer vaccines are another innovative approach designed to train the immune system to identify and respond to cancer cells, much like traditional vaccines prepare the body to fight viruses. Together, these tools are helping the immune system see cancer for what it really is—a dangerous invader that needs to be stopped.
Additionally, researchers are focusing on targeting regulatory T cells (Tregs) and other suppressive elements within the tumor microenvironment. By eliminating these immune-suppressing factors, therapies can reinvigorate the body’s immune system to better fight the cancer.
This shift from blunt-force treatments to precision immunotherapy marks a transformative moment in cancer research. Rather than attacking cancer indiscriminately, researchers are now fine-tuning their approaches to selectively disrupt immune evasion, making treatments more effective and less harmful to healthy tissue.
Cracking Cancer’s Code: What Comes Next
Cancer's sneaky success lies in its ability to stay under the radar by disguising itself. Not only does it do this, but it also requires that the immune system not interfere. It is as if a master of disguise slipped past the guards and took refuge in a well-fortified camp. But science is starting to catch up. Tools like checkpoint inhibitors, CAR T cells, and cancer vaccines are beginning to reveal this intruder and reinforce our immune defenses. The next step? Destroy cancer's hideout itself: the tumor microenvironment. In our next piece, we will dive into the stronghold that cancer builds around itself and explore how scientists are breaching its defenses to bring the immune system back into the fight.
 | A guest post by
|