Patterns of Natural Killer Cell Immune-Reconstitution and Immunological Memory in Patients Affected by Hematologic Malignancies and Undergoing Haploidentical Hematopoietic Stem Cell Transplantation

Zaghi, Elisa (2020). Patterns of Natural Killer Cell Immune-Reconstitution and Immunological Memory in Patients Affected by Hematologic Malignancies and Undergoing Haploidentical Hematopoietic Stem Cell Transplantation. PhD thesis The Open University.



Haploidentical hematopoietic stem cell transplantation (h-HSCT) represents a promising therapeutic approach to cure patients affected by hematologic malignancies. Despite the positive results in terms of overall/disease free survival and reduced tumor relapse, the HLA mismatch between donor and recipient has not been yet fully exploited and the clinical outcome of h-HSCT patients is still hampered by life-threatening side effects, including relapse and viral infections.

In this context, immune cell reconstitution (IR) is certainly key in determining a positive h-HSCT clinical outcome. We demonstrated that Natural Killer (NK) cells represent the first innate lymphocytes recovering after h-HSCT, thus highlighting their role in ensuring a prompt alloreactivity early after the transplant as well as a rapid protection against opportunistic viral infections.

We characterized the predominant and temporary expansion, early after h-HSCT, of a donor-derived unconventional subset of CD56dimCD16neg (unCD56dim) NK cells that is poorly represented in healthy donors. The expression of the inhibitory CD94/NKG2A receptor on all unCD56dim NK cells is associated, at least in part, with NK cell impairment. Indeed, only masking CD94/NKG2A, we observed a recovery of the cytolytic capacity of this NK cell subset. Thus, this inhibitory receptor could represent a potential immunotherapeutic target to improve NK cell alloreactivity after h-HSCT, ensuring a prompt graft versus leukemia (GvL) effect and preventing disease relapse.

However, given the NK cell impairment and the late recovery of adaptive immune cells are responsible for a prolonged immunodeficiency, the increased risk in developing opportunistic infections is high early after h-HSCT. Among them, the human Cytomegalovirus (HCMV) infection/reactivation represents one of the major causes of morbidity and mortality after h-HSCT. In turn, HCMV infection/reactivation can greatly impact NK cell maturation and effector-functions, by providing a rapid expansion of mature, long-lived and hyper-functional NK cells showing memory-like (ml) properties, with unknown origin and unspecific phenotype.

With the aim to investigate the impact of HCMV infection/reactivation on NK cell IR after h-HSCT, we identified a subset of NK cells showing a peculiar CD158b1b2jposNKG2AnegNKG2CposNKp30low phenotype that is expanded only in h-HSCT patients experiencing HCMV reactivation. Interestingly, this latter NK cell population showing memory-like functional features is maintained even after the resolution of the infection and its frequency positively correlates with HCMV viral load and with the numbers of reactivation events. A deeper analysis of our putative ml-NK cell molecular fingerprint revealed that these cells are characterized by an impaired effector-functions, although retaining the capability to produce IFN-γ at transcriptional level.

These findings show in a human setting in vivo the expansion and the kinetic of those NK cells that "remember" the HCMV challenge in patients experiencing viral reactivation. Our data are important to better understand the ability of NK cells to control this life-threatening infection after h-HSCT as well as to exploit their alloreactive responses against tumor burden.

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