How Does the Immune System Recognize and Attack Cancer?
In the first post, we explored the relationship between the immune system and cancer, including how immune cells can recognize and respond to abnormal cells. But recognizing a cancer cell is only the beginning. For the immune system to successfully eliminate a tumor, immune cells must identify the right targets, become activated, reach the tumor, and remain functional despite the defenses cancer develops against them.
This raises an important question: how does the immune system distinguish a cancer cell from a healthy cell, and what happens after that recognition occurs?
Understanding this process provides an important foundation for cancer immunology and helps explain why researchers are developing therapies that harness, strengthen, and redirect the body's own immune response.
Immune Surveillance: Detecting Abnormal Cells
The human body contains an enormous number of cells, each carrying out specialized functions while constantly producing and displaying molecular information. The immune system uses this information to monitor tissues and identify cells that may be infected, damaged, or otherwise abnormal.
Cancer can disrupt the normal molecular characteristics of a cell. Mutations may cause a tumor cell to produce altered proteins, produce unusually high levels of certain proteins, or express proteins in abnormal patterns. These changes can create tumor-associated antigens or tumor-specific antigens that distinguish cancer cells from healthy tissue.
This process of continuously monitoring cells for abnormal characteristics is often referred to as immune surveillance.
However, detecting a potential tumor antigen does not automatically result in the death of a cancer cell. The immune system needs a mechanism for presenting these molecular signals to immune cells and determining whether they warrant an immune response.
How T Cells Recognize Cancer
The immune response against cancer can be understood through the cancer-immunity cycle, a series of 7 steps in which the immune system recognizes and responds to tumor cells. This process is self sustaining, because the death of tumor cells in one cycle releases more antigens to restart the immune response.
The cycle begins when cancer cells die, releasing proteins and other molecules into the surrounding tumor microenvironment. Among these are tumor antigens, which are features that can help distinguish cancer cells from healthy cells. Some of these are neoantigens, unique proteins produced by cancer cells as a result of mutations, which can therefore provide new targets for the immune system.
These antigens are captured by antigen-presenting cells (APCs), particularly dendritic cells (DCs). The DCs process the tumor antigens into smaller peptide fragments and present them on major histocompatibility complex (MHC) molecules. They then travel to lymph nodes, where these antigen-MHC complexes can be recognized by T cells.
T cells recognize these complexes through their T-cell receptors (TCRs). When the appropriate antigen is recognized along with the signals required for activation, tumor-specific T cells become activated and begin to multiply. This produces a population of T cells capable of responding to cancer cells carrying the same antigen.
The activated T cells then leave the lymph nodes and enter the bloodstream. Chemical signals released by the tumor and surrounding tissue help guide them toward the tumor, a process known as T-cell trafficking. Once they reach the tumor, they must move out of the blood vessels and into the tumor tissue, a process known as T-cell infiltration.
Inside the tumor, the T cells search for cells displaying the antigen they were activated against. CD8+ cytotoxic T cells can recognize tumor-associated peptides presented on MHC class I molecules on cancer cells. Once the correct target is identified, these T cells can release cytotoxic molecules, such as perforin and granzymes, leading to the death of the targeted cancer cell.
The process then restarts. As additional tumor cells die, they release more antigens that can be taken up by antigen-presenting cells and used to stimulate further immune responses.
Pathway: Tumor-cell death → antigen release → antigen presentation → T-cell activation → T-cell trafficking → T-cell infiltration → tumor-cell recognition and killing → back to antigen release
Cancer can interfere with several of these stages, which is one reason for continued tumor growth despite being recognized by the immune system. Understanding where and how these failures occur has become an important focus of cancer research, and has helped throughout the development of therapies.
How Cancer Escapes Immune Attack
Cancer cells are constantly changing as they accumulate genetic and molecular adaptations. This creates a constantly changing environment where tumor cells that are particularly vulnerable to immune attack may be eliminated, while cells with characteristics that allow them to evade the immune response can survive. Over time, this can contribute to the development of tumors that are increasingly difficult for the immune system to control.
Cancer cells can interfere with immune recognition in several ways. Some may reduce the presentation of tumor-associated antigens, making them harder for T cells to recognize. Others can alter the molecules involved in immune signaling or produce factors that suppress immune-cell activity.
Cancer can also take advantage of immune checkpoints. Immune checkpoints are regulatory pathways that, in healthy cells prevent the immune system from becoming excessively activated. They are critical for maintaining immune tolerance and protecting healthy tissues from unnecessary damage: Two well-known checkpoint pathways involve PD-1/PD-L1 and CTLA-4. When these pathways are activated, they can reduce T-cell activity.
Tumors can exploit this natural regulatory system. For example, increased PD-L1 expression by tumor or surrounding cells can contribute to suppression of T-cell activity through PD-1 signaling. This creates an important distinction:
A tumor can be recognized by the immune system without being successfully eliminated by it.
The Tumor Microenvironment
Immune recognition also does not occur in isolation.
A tumor contains much more than just cancer cells. Tumor tissue can include T cells, macrophages, fibroblasts, endothelial cells, and other immune and stromal populations, all interacting with one another and with the cancer cells.
Together, these components form the tumor microenvironment (TME).
The TME can strongly influence the outcome of an immune response. It can affect whether immune cells are able to enter the tumor, whether they remain active once they arrive, and how effectively they interact with cancer cells. The physical and chemical conditions within tumors can also differ substantially from those in healthy tissue. Factors such as limited oxygen availability (hypoxia), altered metabolism, and immunosuppressive signaling can create additional challenges for immune cells.
This means that effective anti-tumor immunity depends on multiple factors rather than only having T cells capable of recognizing a cancer antigen.
These challenges explain why some cancers respond well to immunotherapy while others remain resistant.
Conclusion
The immune system has a sophisticated ability to detect abnormalities associated with cancer. Through antigen presentation and highly specific T-cell receptors, immune cells can recognize tumor-associated signals and, under the right conditions, eliminate abnormal cells.
But cancer is capable of adaptation. Tumor cells can alter antigen presentation, exploit immune checkpoints, and create an environment that makes effective immune responses more difficult.
The goal of modern cancer immunotherapy is to understand the immune response well enough to strengthen it, redirect it, or entirely remove the barriers preventing it from functioning effectively.
Comments