The Tumor Microenvironment in Post-Transplant Lymphoproliferative Disorders

Abstract

Post-transplant lymphoproliferative disorders (PTLDs) cover a broad spectrum of lymphoproliferative lesions arising after solid organ or allogeneic hematopoietic stem cell transplantation. The composition and function of the tumor microenvironment (TME), consisting of all non-malignant constituents of a tumor, is greatly impacted in PTLD through a complex interplay between 4 factors: 1) the graft organ causes immune stimulation through chronic antigen presentation; 2) the therapy to prevent organ rejection interferes with the immune system; 3) the oncogenic Epstein-Barr virus (EBV), present in 80% of PTLDs, has a causative role in the oncogenic transformation of lymphocytes and influences immune responses; 4) interaction with the donor-derived immune cells accompanying the graft. These factors make PTLDs an interesting model to look at cancer-microenvironment interactions and current findings can be of interest for other malignancies including solid tumors. Here we will review the current knowledge of the TME composition in PTLD with a focus on the different factors involved in PTLD development.

Keywords: Epstein-Barr virus; Microenvironment, immunosuppression; Post-transplant lymphoproliferative disorders.

Fig. 1

Major microenvironment influencing factors. A schematic overview of the 4 major factors influencing the tumor microenvironment in post-transplant lymphoproliferative disorders. The Epstein-Barr virus has multiple para- and autocrine effects; chronic antigen stimulation leads to T-cell exhaustion; iatrogenic immunosuppression causes T-cell depletion and possible interactions between host derived and (co-)transplanted donor immune cells need to be further investigated

Fig. 2

Representative cases. Representative cases of primary infectious mononucleosis in an immunocompetent young adult (column 1), infectious mononucleosis-like reactivation in a PT-patient (column 2), DLBCL in an immunocompetent patient (column 3) and PT-DLBCL highlighting the similarities between the different lesions. (a-d) hematoxylin and eosin stain; (e-f) Pax5 IHC stains and (g-h) CD20 IHC stains marking B cells; (i-l) CD8 IHC stains marking cytotoxic T cells; (m-o) PD-1 IHC stains and (q-t) PD-L1 IHC stains marking immune checkpoint therapy targets, the cutouts in (m-n) illustrate the difference in PD-1 staining intensity between cytotoxic T cells and follicular T-helper cells; (u-x) CD163 IHC stains marking macrophages; (y-aa) EBV RNA (EBER) in situ hybridization marking EBV presence; (ab) ZEBRA[BZLF] IHC stain for lytic viral replication. Abbreviations; IM: Infectious mononucleosis; LPD: lymphoproliferative disorder; IC: immune competent; DLBCL: diffuse large B-cell lymphoma; PT: post-transplant; scale bar = 100 μm; IHC, immunohistochemical