Innate Immune Responses in the Outcome of Haploidentical Hematopoietic Stem Cell Transplantation to Cure Hematologic Malignancies

Abstract

In the context of allogeneic transplant platforms, human leukocyte antigen (HLA)-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents one of the latest and most promising curative strategies for patients affected by high-risk hematologic malignancies. Indeed, this platform ensures a suitable stem cell source immediately available for virtually any patents in need. Moreover, the establishment in recipients of a state of immunologic tolerance toward grafted hematopoietic stem cells (HSCs) remarkably improves the clinical outcome of this transplant procedure in terms of overall and disease free survival. However, the HLA-mismatch between donors and recipients has not been yet fully exploited in order to optimize the Graft vs. Leukemia effect. Furthermore, the efficacy of haplo-HSCT is currently hampered by several life-threatening side effects including the onset of Graft vs. Host Disease (GvHD) and the occurrence of opportunistic viral infections. In this context, the quality and the kinetic of the immune cell reconstitution (IR) certainly play a major role and several experimental efforts have been greatly endorsed to better understand and accelerate the post-transplant recovery of a fully competent immune system in haplo-HSCT. In particular, the IR of innate immune system is receiving a growing interest, as it recovers much earlier than T and B cells and it is able to rapidly exert protective effects against both tumor relapses, GvHD and the onset of life-threatening opportunistic infections. Herein, we review our current knowledge in regard to the kinetic and clinical impact of Natural Killer (NK), γδ and Innate lymphoid cells (ILCs) IRs in both allogeneic and haplo-HSCT. The present paper also provides an overview of those new therapeutic strategies currently being implemented to boost the alloreactivity of the above-mentioned innate immune effectors in order to ameliorate the prognosis of patients affected by hematologic malignancies and undergone transplant procedures.

Keywords: alloreactivity; haploidentical hematopoietic stem cell transplantation; immune-reconstitution; innate lymphocytes; innate lymphoid cells; natural killer cells; γδ T cells.

Figure 1

Targeting γδ T, Natural Killer, and Innate Lymphoid cells in haplo-HSCT. (1–3) MHC-independent activation of innate immune cells: γδ T lymphocytes (1) and NK cells (2) can kill hematologic tumors by direct cytotoxicity and cytokine secretion. Innate Lymphoid cells (ILCs and ILC3 in particular) (3) play an indirect role in the clearance of tumors cells by improving both thymic regeneration and T cell maturation via their secretion of IL-22. (4–6) Novel therapeutic strategies implemented to enhance NK and γδ T cell alloreactivity against cancer: administration of monoclonal antibodies (mAbs) against NK cell inhibitory checkpoints (4); use of cytokines and zoledronic acid to activate γδ T cells (5); CAR editing and genetic engineering of γδ T and CAR on NK cells (6). (7) Ad hoc manipulation/editing/engineering of ILCs in transplant setting have not yet been explored.