Immune checkpoint protein expression of PD-1 shows prognostic significance in large B-cell lymphomas of the central nervous system

Large B-cell lymphomas of the central nervous system are rare but aggressive neoplasms that uniquely involve immune privileged sites. Targeted immune-based therapies are limited, but immune checkpoint inhibition involving programmed cell death protein 1 (PD-1) and its ligand (PD-L1) are being investigated for relapse/refractory disease. However, the prognostic significance of PD-1 and PD-L1 expression across primary and secondary presentations (PCNSL and SCNSL, respectively) is unknown. We evaluated the prognostic indicators of PD-1 and PD-L1 immunohistochemical expression in a rural-based clinical cohort of both PCNSL and SCNSL. We performed immunohistochemical studies (IHC) for PD-1 (NAT 105, Cell Marque) and PD-L1 (SP263, Ventana) on a curated cohort of CNS lymphomas (n=36) from a rural patient population with PCNSL (n=27) or SCNSL (n=9). Positivity was defined as ≥5% cellular staining. Clinical groups were stratified by patient age, therapy response (durable response- DR or relapse/refractory- RR), and PD-1/PD-L1 IHC expression. All survival analyses were conducted on 33 evaluable patients, none of whom received immune checkpoint inhibitors. Prognostic indicators of overall survival (OS), progression-free survival (PFS), time to progression (TTP), and time to response (TTR) were evaluated and associated with PD-1/PD-L1 expression using Kaplan-Meier methods, log-rank tests, and unadjusted Cox proportional hazards models. Our analysis revealed robust expression rates for PD-1 (67%) and PD-L1 (75%) across all tumors. Importantly, in PCNSL, PD-1 positivity was significantly associated with shorter OS. In the PD-1-positive subgroup, PCNSL exhibited significantly longer PFS/TTP than SCNSL. In addition, there was stratification of OS and PFS by DR and RR clinical status across all tumors, with DR exhibiting longer OS and PFS than RR tumors. Interestingly, PD-1 positivity was associated with faster TTR, particularly for PCNSL, indicating earlier treatment response than SCNSL. PD-L1 expression was not significantly associated with survival outcomes or treatment response. While age was not associated with PFS overall, SCNSL patients older than 65 showed a trend toward shorter PFS. PFS and TTP were identical in this dataset. In conclusion, PD-1 positivity in large B-cell lymphomas of the CNS, particularly for primary presentations, is predictive of earlier treatment response without translating to improved OS or PFS/TTP. These findings highlight the importance of clinical context (disease presentation and extent) and suggest that early-response kinetics like TTR offer complementary biological insight distinct from long-term survival outcomes. Larger studies are needed to further define the prognostic influence of immune checkpoint proteins in large B-cell lymphomas of immune-privileged sites.