Immune checkpoint inhibition plays a significant and evolving role in the treatment of non-Hodgkin’s lymphoma (NHL), a diverse group of blood cancers originating from lymphocytes. The immune system naturally has built-in “checkpoints”—molecules on immune cells that act like brakes to prevent overactivation and autoimmunity. Cancer cells, including those in NHL, can exploit these checkpoints to evade immune attack by turning off the immune response against them. Immune checkpoint inhibitors (ICIs) are drugs designed to block these inhibitory signals, thereby reactivating the immune system to recognize and destroy cancer cells.
In NHL, immune checkpoint inhibition primarily targets molecules such as PD-1 (programmed cell death protein 1) and its ligand PD-L1, as well as CTLA-4 (cytotoxic T-lymphocyte-associated protein 4). These checkpoints normally serve to dampen T cell activity after an immune response, but in lymphoma, their overexpression on tumor cells or immune cells in the tumor microenvironment suppresses the anti-tumor immune response. By blocking PD-1/PD-L1 or CTLA-4 pathways, ICIs restore the function of tumor-infiltrating lymphocytes (TILs), enabling them to attack lymphoma cells more effectively.
The role of immune checkpoint inhibition in NHL is complex due to the heterogeneity of the disease. Some subtypes of NHL, such as primary mediastinal large B-cell lymphoma and certain types of Hodgkin lymphoma, have shown remarkable responses to ICIs. This is partly because these lymphomas often have high expression of PD-L1 or genetic alterations that increase immune evasion. In contrast, many other NHL subtypes have been less responsive, likely due to differences in their tumor microenvironment, lower expression of checkpoint molecules, or other mechanisms of immune resistance.
One of the challenges in NHL treatment with ICIs is the tumor microenvironment, which includes various immune cells, stromal cells, and signaling molecules that can either support or inhibit immune responses. Some NHL tumors create an immunosuppressive environment by recruiting regulatory T cells, myeloid-derived suppressor cells, or by secreting inhibitory cytokines, all of which can blunt the effectiveness of checkpoint blockade. Therefore, ongoing research aims to understand these interactions better and develop combination therapies that can overcome resistance, such as pairing ICIs with chemotherapy, targeted agents, or other immunotherapies.
Another important aspect is the identification of biomarkers that predict which NHL patients will benefit most from immune checkpoint inhibition. PD-L1 expression, tumor mutational burden, and the presence of TILs are among the factors studied to guide treatment decisions. However, these markers are not yet definitive, and clinical trials continue to refine patient selection.
In summary, immune checkpoint inhibition reactivates the immune system’s ability to fight non-Hodgkin’s lymphoma by blocking inhibitory pathways that cancer cells exploit. While it has transformed treatment for some lymphoma subtypes, its efficacy varies widely, and research is ongoing to enhance its effectiveness and broaden its applicability through combination strategies and better patient selection.
