Natural Killer Cells in Post-Transplant Lymphoproliferative Disorders

Abstract

Post-transplant lymphoproliferative disorders (PTLDs) are life-threatening complications arising after solid organ or hematopoietic stem cell transplantations. Although the majority of these lymphoproliferations are of B cell origin, and are frequently associated with primary Epstein-Barr virus (EBV) infection or reactivation in the post-transplant period, rare cases of T cell and natural killer (NK) cell-originated PTLDs have also been described. A general assumption is that PTLDs result from the impairment of anti-viral and anti-tumoral immunosurveillance due to the long-term use of immunosuppressants in transplant recipients. T cell impairment is known to play a critical role in the immune-pathogenesis of post-transplant EBV-linked complications, while the role of NK cells has been less investigated, and is probably different between EBV-positive and EBV-negative PTLDs. As a part of the innate immune response, NK cells are critical for protecting hosts during the early response to virus-induced tumors. The complexity of their function is modulated by a myriad of activating and inhibitory receptors expressed on cell surfaces. This review outlines our current understanding of NK cells in the pathogenesis of PTLD, and discusses their potential implications for current PTLD therapies and novel NK cell-based therapies for the containment of these disorders.

Keywords: Epstein–Barr virus; natural killer cells; post-transplant lymphoproliferative disorders.

Figure 1

Natural killer (NK) cells are the first lymphocyte compartment to be quantitatively and functionally restored after solid organ or hematopoietic stem-cell transplantation and are the first line of protection against Epstein–Barr virus (EBV)-infected cells and tumor development. At the recognition of EBV-infected or tumor targets, NK cells release perforin and granzymes to mediate the lysis of target cells. Meanwhile, NK cells produce IFN-γ to limit viral infection. Transplant recipients with increasing EBV loads are at high risk of EBV-positive PTLD development and are often treated with rituximab, a monoclonal antibody (mAb) that binds to the CD20 molecule expressed at the surface of B cells. In such cases, NK cells also contribute to the defense of the host by inducing antibody-dependent cell cytotoxicity (ADCC) though the recognition of therapeutic mAbs by CD16. However, solid organ transplantation (SOT) recipients often present increased proportions of NK cells expressing the PD-1 inhibiting immune checkpoint receptor in relation with high EBV loads in blood. During EBV-positive post-transplant lymphoproliferative disorders (PTLDs), NK cells progressively increase PD-1 expression together with the NKG2A inhibiting receptor, while NKG2D and NKp46 activating receptors are downmodulated, a phenotype that might impact NK cell functional capacity against the tumor. In addition to this phenotype, constant NK cell activation has been observed and related to increased activation-induced cell death (AICD), resulting in peripheral NK cell lymphopenia at PTLD diagnosis. In the case of EBV-negative PTLDs, NK cells show increased expression of the Tim-3 inhibiting immune checkpoint receptor, and increased apoptosis has also been associated with mild NK cell lymphopenia at EBV-negative PTLD diagnosis. Besides their central role as cytotoxic innate lymphocytes, NK cells can also be exploited for therapeutic use. Their most frequent role is their cytotoxic activity through ADCC in the context of mAb treatments such as chimeric (rituximab) or humanized (obinutuzmab) anti-CD20 mAbs. Furthermore, autologous infusions of activated NK cells have been used in HSCT recipients with PTLD. Currently, several strategies for NK cell activity enhancement are under development and present characteristics that could allow their utilization in transplanted populations. Bi-specific and tri-specific NK cell engagers, for example, facilitate NK cell synapsing with tumor targets in a very specific manner, and offer the advantage that they can be administered to boost NK cell responses of the host or be coupled with either autologous or allogeneic infusions of NK cells. CAR-NK cells, on the other hand, promise an “off-the-shelf” cellular therapy, so far showing low toxicity and high specificity in immunocompetent recipients.