Could Immune Checkpoint Disorders and EBV Reactivation Be Connected in the Development of Hematological Malignancies in Immunodeficient Patients?

SIMPLE SUMMARY: Primary immunodeficiencies (PIDs) and secondary immunodeficiencies (SIDs) weaken the immune system, making people prone to infections and possibly affecting cancer development. Epstein–Barr virus (EBV), a common virus, is linked to cancer, especially in those with weak immunity. This study compares immune factors like PD-1/PD-L1, CTLA-4/CD86, CD200R/CD200, and EBV in chronic lymphocytic leukemia (CLL, a SID) and common variable immunodeficiency (CVID, a PID). We studied CLL, CVID, and healthy people, checking EBV activity and immune checkpoints. Both CLL and CVID patients showed more EBV activity, and their immune checkpoints were changed, possibly affecting EBV and immunity. This study shows how immune issues, EBV, and checkpoints might contribute to cancer in people with weakened immunity. It suggests ways to manage these risks. More research is needed to understand this fully and develop treatments. ABSTRACT: Primary immunodeficiencies (PIDs) and secondary immunodeficiencies (SIDs) are characterized by compromised immune function, rendering individuals susceptible to infections and potentially influencing cancer development. Epstein–Barr virus (EBV), a widespread herpesvirus, has been linked to cancer, particularly in those with weakened immune systems. This study aims to compare selected immune parameters, focusing on immune checkpoint molecules (PD-1/PD-L1, CTLA-4/CD86, CD200R/CD200), and EBV reactivation in patients with chronic lymphocytic leukemia (CLL, a representative of SIDs) and common variable immunodeficiency (CVID, a representative of PIDs). We performed a correlation analysis involving patients diagnosed with CLL, CVID, and a healthy control group. EBV reactivation was assessed using specific antibody serology and viral load quantification. Peripheral blood morphology, biochemistry, and immunophenotyping were performed, with emphasis on T and B lymphocytes expressing immune checkpoints and their serum concentrations. Our findings revealed elevated EBV reactivation markers in both CLL and CVID patients compared with healthy controls, indicating increased viral activity in immunodeficient individuals. Furthermore, immune checkpoint expression analysis demonstrated significantly altered percentages of T and B lymphocytes expressing PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200 in CLL and CVID patients. This suggests a potential interplay between immune checkpoint dysregulation and EBV reactivation in the context of immunodeficiency. In conclusion, our study underscores the intricate relationship between immune dysfunction, EBV reactivation, and immune checkpoint modulation in the context of immunodeficiency-associated cancers. The altered expression of immune checkpoints, along with heightened EBV reactivation, suggests a potential mechanism for immune evasion and tumor progression. These findings provide insights into the complex interactions that contribute to cancer development in immunocompromised individuals, shedding light on potential therapeutic targets for improved management and treatment outcomes. Further investigations are warranted to elucidate the underlying mechanisms and to explore potential interventions to mitigate cancer risk in these patient populations.