PD‐L1 and PD1 expression in post‐transplantation lymphoproliferative disease (PTLD) of childhood and adolescence: An inter‐ and intra‐individual descriptive study covering the whole spectrum of PTLD categories

Abstract

Therapy of children with post‐transplantation lymphoproliferative disorder (PTLD) after hematopoietic stem cell (HSCT) and solid organ transplantation (SOT) can be challenging. In this retrospective study, we investigated PD‐L1 and PD1 expression in all PTLD categories of childhood and adolescence to see whether checkpoint inhibition with PD‐L1/PD1 inhibitors may serve as a therapy option. We included 21 patients aged 19 years or younger (at date of transplant) with PTLD following SOT or HSCT having adequate tumor samples available (n = 29). Using immunohistochemistry, we evaluated PD‐L1/PD1 expression on both tumor cells and cells of the microenvironment in all samples. Availability of consecutively matched tumor samples during 6 of 21 patients' disease courses also allowed an intra‐individual assessment of PD‐L1/PD1 expression. We observed lower PD‐L1 and higher PD1 expression in non‐destructive lesions, and higher PD‐L1 and lower PD1 expression in polymorphic and, in particular, in monomorphic PTLD, mostly diffuse large B‐cell lymphomas (DLBCL, n = 10/21). The amount of PD‐L1‐ and PD1‐positive cells changed in the opposite way in sequential biopsies of the same individual correlating well with the PTLD category. This is the first comprehensive pediatric study assessing PD‐L1 and PD1 expression on tumor cells and in the microenvironment of PTLD including not only monomorphic, but also non‐destructive early lesions. PD‐L1 expression of the tumor cells inversely correlated with PD1 expression in surrounding tissues, with the highest expression in DLBCL. Since PTLD can be therapeutically challenging, our results indicate a potential efficacy of checkpoint inhibitors if standard immune‐ and/or chemotherapy fail or are impossible. We therefore recommend routine staining of PD‐L1 and PD1 in all PTLD categories.

Programmed cell death ligand 1 expression in aggressive pediatric non-Hodgkin lymphomas: frequency, genetic mechanisms, and clinical significance

“…29,31 The frequency of PD-L1 positive pediatric PTLD-DLBCL cases (72.7%) was similar to other pediatric and adult PTLD-DLBCL cohorts that reported approximately 60-80% positivity. 13,34,41 Despite defining 5% as the threshold for PD-L1-positivity, all PD-L1-positive cases in our cohort showed at least 30% positive membranous staining. Kiyasu et al 29 employed a similar cut-off in adult DLBCL and reported PD-L1 positivity ranges from 30% to 100% while observing a marked decrease in staining below the 30% threshold.…”

“…PD-1 IHC staining (clone MRQ-22, Cell Marque) was performed at a 1:50 dilution on an automated Leica Bond III immunostainer. All PD-1/PD-L1 IHC results were independently reviewed and scored by two hematopathologists as previously described 34 with a few modifications (Supplemental Table 1). Membranous PD-L1 staining of tumor cells and macrophages, and membranous PD-1 staining of tumor infiltrating lymphocytes (TIL) were scored for staining intensity: 0 (no staining), 1+ (weak or equivocal), 2+ (moderate), 3+ (strong).…”

The Association Between Single-Nucleotide Polymorphisms of Co-Stimulatory Genes Within Non-HLA Region and the Prognosis of Leukemia Patients With Hematopoietic Stem Cell Transplantation

“…Maintenance of graft tolerance is related to the interaction between PDCD1 (PD-1) and PD-L ( 43 ). Post-transplantation lymphoproliferative disorder, which was developed under the condition of T-cell dysfunction or immunosuppression after HSCT, is also related to the expression of PDCD1 ( 44 ). Among the SNPs, rs5839828 and rs36084323 are within the promoter region, rs6705653 and rs41386349 are in intron 4, and rs2227982 is in exon 5.…”

Posttransplant Lymphoproliferative Disorder Following Kidney Transplantation: A Review

“…The potential use of checkpoint inhibition in patients with PTLD has been fueled by the high expression of PD-1 (programmed cell death 1 protein) and PD-L1 (programmed cell death 1 ligand 1) in PTLDs, in particular in EBV-positive cases, which are mainly driven by 9p24.1 gain/amplification. [67][68][69][70] However, switching on the immune system may cause a substantial risk for graft rejection, and this may also complicate the use of chimeric antigen receptor T-cell (CAR-T) therapy, given the potentially impressive cytokine storm associated with this therapy. Krishnamoorthy et al recently reported on the use of CAR-T in solid organ transplantation-related PTLD (including 2 KTRs).…”