Immunotherapy in Hodgkin Lymphoma: Molecular Mechanisms and Clinical Implications

Hodgkin lymphoma (HL) is a type of lymphoma characterized by the presence of Reed-Sternberg cells. The treatment landscape for HL has evolved significantly, with immunotherapy emerging as a groundbreaking approach. This article explores the molecular mechanisms of immunotherapy in treating Hodgkin lymphoma and its clinical implications. Immunotherapy leverages the body's immune system to combat cancer cells. In Hodgkin lymphoma, two primary immunotherapeutic strategies have gained prominence: checkpoint inhibitors and monoclonal antibodies. Checkpoint inhibitors have revolutionized HL treatment by targeting the PD-۱/PD-L۱ pathway. Programmed death-۱ (PD-۱) is a checkpoint protein on T cells that, when bound to its ligand PD-L۱, inhibits T cell activity, thus allowing cancer cells to evade the immune response. In HL, the overexpression of PD-L۱ on Reed-Sternberg cells is common, making this pathway a critical target. Nivolumab and pembrolizumab, two PD-۱ inhibitors, have shown remarkable efficacy in patients with relapsed or refractory HL. By blocking PD-۱, these drugs restore T cell activity, enabling the immune system to recognize and destroy cancer cells. The molecular mechanisms of the PD-۱/PD-L۱ interaction involve complex signaling pathways. When PD-۱ binds to PD-L۱, it recruits SHP-۲ phosphatase, leading to the dephosphorylation of key molecules like PI۳K and Akt. This results in the inhibition of the Akt/mTOR pathway, which in turn reduces T cell proliferation and cytokine production. Inhibiting PD-۱ prevents this negative signaling cascade, thereby reactivating T cells. Monoclonal antibodies represent another cornerstone of immunotherapy in HL. Brentuximab vedotin, an antibody-drug conjugate, targets CD۳۰, a cell surface antigen expressed on Reed-Sternberg cells. Brentuximab vedotin consists of an anti-CD۳۰ monoclonal antibody linked to monomethyl auristatin E (MMAE), a cytotoxic agent. Upon binding to CD۳۰, the conjugate is internalized by the cancer cell, where MMAE is released and disrupts microtubule formation, leading to cell cycle arrest and apoptosis. This targeted approach minimizes damage to healthy cells and enhances the specificity of cancer treatment. Emerging research highlights the tumor microenvironment (TME) in modulating the efficacy of immunotherapy. The TME in HL is rich in immune cells, including T cells and macrophages. However, Reed-Sternberg cells can create an immunosuppressive TME, secreting cytokines like TGF-β and IL-۱۰, which inhibit T cell function and attract regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Targeting these immunosuppressive components is essential for enhancing the anti-tumor immune response. Resistance to PD-۱ inhibitors presents significant challenges. This resistance can develop through genetic mutations in the JAK-STAT pathway, which can increase PD-L۱ expression independently of immune signaling. Furthermore, alterations in antigen presentation machinery, such as mutations in beta-۲ microglobulin, can reduce T cell recognition of cancer cells. In conclusion, immunotherapy has transformed Hodgkin lymphoma treatment by targeting molecular pathways involved in immune evasion. Checkpoint inhibitors like nivolumab and pembrolizumab, along with monoclonal antibodies like brentuximab vedotin, provide substantial clinical benefits. Understanding the molecular mechanisms behind these therapies enhances their application and informs the development of next-generation immunotherapeutics. As research progresses, integrating immunotherapy with traditional treatments holds promise for improving patient outcomes in Hodgkin lymphoma.

کلیدواژه ها:

Hodgkin Lymphoma ، Immunotherapy ، Checkpoint Inhibitors ، PD-۱ ، Nivolumab