Estudo da expressão dos marcadores imunológicos PD-1, PD-L1E CTLA-4 em pacientes com linfoma de Hodgkin clasico

Abstract

Hodgkin's Lymphoma (HL) originates in the lymphatic system, a complex made up of organs and tissues responsible for the production of immune cells and vessels that transport these cells throughout the body. Immune checkpoint proteins are overexpressed in HL. In this context, the tumor expression of PD-1, PD-L1, PD-L2, and CTLA-4 may emerge as potential predictive biomarkers for immunotherapy response in HL. The study aimed to evaluate the expression of PD-1, PD-L1, and CTLA-4 proteins in HL patients, correlating them with clinical markers, prognostic scores, and treatment. This is a quantitative and retrospective study of patients with a histopathological diagnosis of HL. A total of 52 HL patients were selected based on criteria, including undergoing oncological treatment at Walter Cantídio University Hospital (HUWC), being adults of both genders, aged 18 or older, diagnosed between 2015 and 2019. Sociodemographic, clinical, and laboratory data were obtained from medical records. Immunohistochemistry using automated techniques with lymph node biopsies from HL patients was employed to analyze the expression of PD-1, PD-L1, and CTLA-4 proteins.Most patients were under 29 years old (67.31%), with 55.77% females and 44.23% males. The most prevalent clinical stage was Stage II (40.38%), and the B type of symptomatology was predominant (76.92%). The majority had nodular sclerosis (73.08%) and mixed cellularity (19.23%). A good prognostic IPS with scores 2 and 3 was observed in 71.15% of cases. Protein expression was positive in 50%, 86.54%, and 75% in HL patient lymph node biopsies. Regarding the intensity of marking, 21.15% showed strong PD-1 protein marking, 36.46% showed strong PD-L1 marking, and for CTLA4, the majority of patients (36.54%) had weak marking of this protein. In the analysis of protein expression association with sociodemographic and clinical variables, no association was observed between gender and age with positive

expression of PD-1, PD-L1, and CTLA4 (p>0.05). Increased protein expression of PD- 1 was associated with a complete response to the first treatment (p=0.042) and no

need for a second therapy (p=0.008). Positive PD-L1 expression was associated with exclusive ABVD use (p=0.046), and positive CTLA4 expression was associated with no mediastinal involvement (p=0.049), a complete response to the second treatment (p=0.023), and a complete response in the final condition of the HL patient (p=0.045). Positive PD-1 expression with moderate marking intensity was associated with shorter progression-free survival (PFS) with a median of 1.53 years for both analyses up to 10

years (p=0.0001) and 5 years (p=0.00027). No association was observed between PD- 1, PD-L1, and CTLA-4 expression with overall survival (OS). In conclusion, there was

an increase in the expression of PD-1, PD-L1, and CTLA-4 proteins at diagnosis in HL patients, and these were associated with clinical variables and disease-free survival (DFS), reinforcing the potential biomarker role of these proteins in the treatment and prognosis of HL patients.