EXPRESSION OF PD-1 AND PD-L1 IN DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS WITH PRE-EXISTING RHEUMATOID ARTHRITIS - A POSSIBLE ASSOCIATION WITH HIGH RHEUMATOID ARTHRITIS DISEASE ACTIVITY

BackgroundPatients with rheumatoid arthritis (RA) are at increased risk of developing diffuse large B-cell lymphoma (DLBCL). Immunotherapy blocking programmed cell death protein 1 (PD-1) and its ligand PD-L1 has substantially improved outcome in a number of malignant diseases but has so far been disappointing in DLBCL. However, current research seeks to identify DLBCL subgroups responsive to PD-1 blocking agents. Whether patients with pre-existing rheumatoid arthritis (RA) might constitute such a subgroup is unknown. Expression of PD-1 and PD-L1 has not previously been studied in a cohort of RA-DLBCL patients.ObjectivesTo determine intratumoural expression of PD-1 and PD-L1 in DLBCL patients with pre-existing RA and relate the expression to clinical characteristics and survival outcome.MethodsWe included 103 RA-DLBCL patients and 74 DLBCL controls without rheumatic disease. PD-1 and PD-L1 immunohistochemical markers were applied on tumour tissue microarrays. The number of PD-1+ tumour infiltrating leukocytes (TILs) and proportions of PD-L1+ tumour cells and TILs were calculated and correlated to clinical data. For RA patients, disease activity had been individually scored repeatedly over time based on swollen and tender joint counts, erythrocyte sedimentation rate (ESR), and the treating physician’s global assessment of disease activity from onset of RA until lymphoma diagnosis(1). Values of cumulative disease activity for each patient were calculated as area under the curve (AUC). To investigate a possible influence of RA disease severity on the expression of PD-1 and PD-L1, RA patients with DLBCL were divided in two groups using the upper quartile of the AUC values as cut off for the highest disease activity group.ResultsExpression of PD-1 in TILs and PD-L1 in tumour cells was similar in RA-DLBCL and DLBCL controls. In RA-DLBCL, high expression of PD-L1 in tumour cells was significantly more common in patients with the most severe RA disease (45% vs 20%, p=0.04) (Table 1) and was associated with inferior overall survival in multivariable analysis (HR 4.62, 95% CI, 1.55-13.71).Table 1.Clinical and lymphoma related parameters and their distribution in the RA-DLBCL patients according to high and low expression of PD-L1 in tumour cellsEntire cohortHigh PD-L1 in tumour cells1Low PD-L1 in tumour cellsP-value*All patients, n (%)103 (100)11 (100)89 (100)Women, n (%)61 (59)6 (55)54 (61)0.70Age ≥60, n (%)85 (83)10 (91)72(81)0.68DLBCL subtype, n (%)0.35 GCB30 (29)2 (18)27 (30) Non-GCB69 (67)9 (82)57 (64) Missing4 (4)0 (0)5 (6)Ann Arbor stage III-IV, n (%)65 (63)5 (45)57 (64)0.31Missing4 (4)1 (10)3 (3)EBV status, n (%)<0.001Positive9 (9)4 (36)5 (6)Missing2 (2)0 (0)2 (2)RA highest disease severity group, n (%)0.04 Yes25 (25)5 (45)18 (20) Missing4 (4)1 (10)3 (3)Active RA treatment, n (%)†0.96 Yes39 (38)4 (36)34 (38) Missing3 (3)1 (10)2 (2)RA, rheumatoid arthritis; DLBCL, diffuse large B-cell lymphoma; GCB, germinal centre B-cell like; EBV, Epstein-Barr virus; DMARD, disease modifying anti-rheumatic drug; TIL, tumour-infiltrating leukocytes; 1 High expression ≥17% PD-L1+ tumour cells of all tumour cells; *According to chi-square or Fischer’s exact test; †Active RA treatment= DMARD and/or corticosteroids;ConclusionOur results indicate an association between a more severe RA disease and increased expression of PD-L1 in DLBCL tumour cells. This might have implications for the prognosis of the lymphoma as well as the chance of response to immunotherapy and warrants further studies also in other chronic inflammatory condidions.References[1]Baecklund E, Iliadou A, Askling J, Ekbom A, Backlin C, Granath F, et al. Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum. 2006;54(3):692-701.Disclosure of InterestsNone declared