Mechanisms of Immune Evasion in Breast Cancer
Recent findings in breast cancer research have revealed intricate mechanisms through which cancer cells evade the immune system, contributing to tumor progression and metastasis. One key mechanism is immune evasion through germline-mediated immunoediting. This process begins when cancer cells display abnormal proteins on their surfaces, which normally would alert the immune system’s T cells to destroy them. However, over time, cancer cells can evolve to evade this detection.
Specifically, cells with high germline epitope burden (the ability to display multiple copies of abnormal proteins) initially attract more immune surveillance. At early stages, these tumors are more likely to be eliminated by immune cells. However, as cancer progresses, these tumors develop resistance mechanisms, allowing them to avoid detection by the immune system. This shift often leads to more aggressive cancers with a higher propensity for metastasis .
Additionally, immune checkpoint pathways, such as the PD-1/PD-L1 axis, are often exploited by cancer cells. These pathways act as “brakes” on the immune system, preventing T cells from attacking cancer cells. Breast cancers, particularly aggressive subtypes like triple-negative breast cancer (TNBC), can upregulate the expression of immune checkpoint proteins, effectively turning off the immune response and allowing the tumor to grow unchecked. Immunotherapies that block these pathways are being developed to counteract this evasion, aiming to make these tumors more visible to the immune system again.
In summary, cancer cells develop immune evasion mechanisms, including immunoediting and checkpoint inhibition, which allow them to escape immune detection and become more aggressive over time. These insights are guiding the development of therapies to block these processes and improve cancer treatment outcomes.
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Eduardas Vaigauskas
Cancer cells do not “know” in a conscious sense that they need to change their abnormal proteins. Instead, this process happens through natural selection within the tumor as it grows and interacts with the immune system. Several key mechanisms contribute to cancer cells developing resistance to immune system attacks:
• Immunoediting: Over time, cancer cells that are recognized and targeted by the immune system are more likely to be eliminated, while those with mutations that allow them to evade detection survive and proliferate. This process, called immunoediting, leads to the selection of cancer cells with reduced antigenicity, meaning they express fewer or less detectable abnormal proteins.
• Antigen Loss: Some cancer cells can lose or reduce the expression of the abnormal proteins (antigens) that initially triggered the immune response. This can occur through mutations in genes that encode for those proteins, leading to cells that are less visible to T cells.
• Downregulation of MHC molecules: Cancer cells can downregulate or alter the expression of major histocompatibility complex (MHC) molecules, which are crucial for presenting abnormal proteins to T cells. Without proper MHC expression, the immune system cannot recognize and attack these cells effectively.
• Expression of Immune Checkpoint Proteins: Tumors often upregulate immune checkpoint proteins like PD-L1, which bind to receptors on T cells (e.g., PD-1) and deactivate them. This allows cancer cells to essentially “turn off” the immune response, preventing T cells from attacking.
• Mutation of Immune Evasion Genes: Cancer cells can acquire mutations in genes that regulate immune evasion, such as those involved in the immune checkpoint pathway. These mutations may enhance their ability to escape immune surveillance.
Eduardas Vaigauskas
At early stages, cancer cells with high germline epitope burden (those displaying many abnormal proteins or “antigens”) are more likely to attract immune surveillance. The immune system, particularly T cells, recognizes these abnormal proteins as foreign and attempts to eliminate the cancer cells. However, the process is not always perfect. Several factors can prevent the immune system from completely eliminating all cancer cells with high epitope burden:
• Tumor microenvironment: Some areas of the tumor may have a microenvironment that suppresses immune responses, allowing certain cancer cells to evade detection.
• Immunosuppressive factors: Tumors often release molecules (e.g., cytokines like TGF-β, IL-10) that suppress immune activity, reducing the effectiveness of immune cells in clearing all cancer cells.
• Variability in immune system strength: Not all immune systems are equally effective. Factors like the patient’s age, genetic makeup, or pre-existing health conditions can affect how well the immune system responds to early cancer cells.
Thus, while many cells with high germline epitope burden may be eliminated, some may escape immune surveillance, surviving and continuing to grow.