Non-Hodgkin’s lymphoma (NHL) is a complex group of blood cancers that originate in the lymphatic system, primarily affecting B cells or T cells. One of the most intriguing and challenging aspects of NHL research is understanding how these cancer cells manage to evade the immune system, which is naturally designed to detect and destroy abnormal cells. The immune system’s failure to eliminate lymphoma cells is not just a passive event; rather, it involves active strategies employed by the cancer to escape immune surveillance. Recent research has been increasingly focused on identifying these immune escape mechanisms, which could open new avenues for treatment and improve patient outcomes.
At the heart of immune escape in NHL is the concept that cancer cells can manipulate their environment and the immune system itself to avoid detection and destruction. One key mechanism is known as **immune exclusion**, where lymphoma cells create physical and chemical barriers that prevent immune cells, especially cytotoxic CD8+ T cells, from infiltrating the tumor. These T cells are crucial because they can recognize and kill cancer cells. However, in many NHL cases, the tumor microenvironment becomes hostile to these immune cells. For example, cancer-associated fibroblasts (CAFs) within the tumor produce dense collagen and fibrotic tissue, effectively forming a shield that blocks immune cells from reaching the lymphoma cells. This physical barrier is compounded by the tumor’s ability to suppress the production of chemokines—chemical signals that normally attract immune cells to the tumor site. Without these signals, immune cells are less likely to migrate into the tumor, allowing lymphoma cells to grow unchecked.
Beyond physical barriers, NHL cells can also alter the expression of molecules on their surface to avoid immune recognition. One well-studied example involves mutations in the CD19 protein, a marker commonly found on B cells. CD19 is a target for certain immunotherapies, such as CAR-T cell therapy, which engineers a patient’s own T cells to recognize and kill CD19-expressing lymphoma cells. However, point mutations in CD19 can change its structure, making it invisible to these engineered T cells. This mutation-driven immune escape allows lymphoma cells to survive even after aggressive immunotherapy, posing a significant challenge for treatment.
Another layer of immune escape involves the creation of an immunosuppressive environment within the lymphoma. NHL cells can secrete various cytokines and signaling molecules that dampen the immune response. For instance, elevated levels of interleukin-6 (IL-6) have been observed in some lymphoma cases, contributing to a dysfunctional immune phenotype. This “immune scar” persists even after the lymphoma appears to be in remission, indicating that the cancer leaves a lasting imprint on the immune system. Such an environment not only protects the lymphoma cells but also impairs the ability of immune cells to mount an effective attack.
Research has also uncovered that NHL can manipulate immune checkpoint pathways. These pathways normally serve as brakes on the immune system to prevent overactivation and autoimmunity. Lymphoma cells can exploit these checkpoints, such as PD-1/PD-L1, to turn off T cell activity. By expressing PD-L1, lymphoma cells send inhibitory signals to T cells, effectively telling them to stand down. This immune checkpoint engagement is a sophisticated form of immune escape that has led to the development of checkpoint inhibitor therapies, which aim to block these signals and reactivate the immune response against the tumor.
In addition to these mechanisms, NHL cells may also evade immune detection by altering antigen presentation. Normally, cells display fragments of proteins (antigens) on their surface via molecules called MHC (major histocompatibility complex). These antigens help T cells recognize infected or abnormal cells. Some lymphoma cells reduce or lose MHC expression, making it harder for T cells to identify them as threats. This downregulation of antigen presentation is another stealth tactic that allows lymphoma cells to hide from immune surveillance.
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