The early expansion of anergic NKG2A^pos/CD56^dim/CD16^neg natural killer represents a therapeutic target in haploidentical hematopoietic stem cell transplantation

Abstract

Natural killer cells are the first lymphocyte population to reconstitute early after non-myeloablative and T cell-replete haploidentical hematopoietic stem cell transplantation with post-transplant infusion of cyclophosphamide. The study herein characterizes the transient and predominant expansion starting from the second week following haploidentical hematopoietic stem cell transplantation of a donor-derived unconventional subset of NKp46neg-low/CD56dim/CD16neg natural killer cells expressing remarkably high levels of CD94/NKG2A. Both transcription and phenotypic profiles indicated that unconventional NKp46neg-low/CD56dim/CD16neg cells are a distinct natural killer cell subpopulation with features of late stage differentiation, yet retaining proliferative capability and functional plasticity to generate conventional NKp46pos/CD56bright/CD16neg-low cells in response to interleukin-15 plus interleukin-18. While present at low frequency in healthy donors, unconventional NKp46neg-low/CD56dim/CD16neg cells are greatly expanded in the seven weeks following haploidentical hematopoietic stem cell transplantation, and express high levels of the activating receptors NKG2D and NKp30 as well as of the lytic granules Granzyme-B and Perforin. Nonetheless, NKp46neg-low/CD56dim/CD16neg cells displayed a markedly defective cytotoxicity that could be reversed by blocking the inhibitory receptor CD94/NKG2A. These data open new and important perspectives to better understand the ontogenesis/homeostasis of human natural killer cells and to develop a novel immune-therapeutic approach that targets the inhibitory NKG2A check-point, thus unleashing natural killer cell alloreactivity early after haploidentical hematopoietic stem cell transplantation.

Targeting NKG2A to elucidate natural killer cell ontogenesis and to develop novel immune-therapeutic strategies in cancer therapy

“…Although NK cells reach normal levels and a complete donor chimerism within the first month after allo‐ and haplo‐HSCT, the maturation of NK cells takes longer. Indeed, the distribution of CD56 and CD16 on the surface returns similar to that of healthy donors only after few months from the transplant.…”

“…Instead, the frequency of CD56 br NK cells early after HSCT is remarkably higher than that of CD56 dim , thus further confirming the developmental relationship between these two NK cell subsets. Moreover, we recently reported that the low frequency of CD56 dim NK cells in the first weeks following HSCT is counterbalanced by the expansion of an unconventional NK cell subsets characterized by a CD56 dim /CD16 neg phenotype (uCD56 dim ) . The frequency of this latter NK cell population is very low under homeostatic conditions, although it is endowed with a remarkably high cytotoxicity .…”

“…The frequency of this latter NK cell population is very low under homeostatic conditions, although it is endowed with a remarkably high cytotoxicity . In contrast, the uCD56 dim NK cells reconstituting in the recipients early after haplo‐HSCT are strongly impaired in their alloreactive effector functions due to the constitutive and transient high levels of NKG2A expression . Hence, it is conceivable to hypothesize that uCD56 dim NK cells could represent an additional or an alternative step in NK cell differentiation.…”

“…In contrast, the uCD56 dim NK cells reconstituting in the recipients early after haplo‐HSCT are strongly impaired in their alloreactive effector functions due to the constitutive and transient high levels of NKG2A expression . Hence, it is conceivable to hypothesize that uCD56 dim NK cells could represent an additional or an alternative step in NK cell differentiation. Although the developmental relationship between uCD56 dim and CD56 br still remains to be elucidated, the high expression of NKG2A likely plays an important role in terminal NK cell maturation.…”

“…The disclosure of potential alloreactive uCD56 dim NK cells expanded early after allo‐ and haplo‐HSCT has arisen new important questions. Indeed, the constitutive expression of CD94/NKG2A on almost all NK cells early after HSCT represents a novel targetable immune‐checkpoint to boost NK cell alloreactivity early after transplant in order to prevent acute and chronic GvHD, the onset of opportunistic infection and to ensure an optimal engraftment …”