Phd in IINNOVATION IN IMMUNO-MEDIATED AND HEMATOLOGICAL DISORDERS

Thesis title: Role of donor clonal hematopoiesis-related mutations in recipients’ immunologic recovery after allogeneic stem cell transplantation

Clonal hematopoiesis (CH) occurs in the blood of approximately 20% of individuals older than 40 years, and when present with variant allele frequency >2%, it is categorized as clonal hematopoiesis of indeterminate potential (CHIP). However, the effect of smaller clones in the general population is unknown. It has been recently demonstrated that CH can engraft from an older donor to the allogeneic stem cell transplant (HSCT) recipient. Several studies showed a benefit in progression-free survival and relapse risk, with higher incidence of chronic graft-versus-host-disease (GVHD) in patients transplanted from donors harboring DNMT3A mutations (DNMT3A-CH), the most common mutation in CH. Herein, we carried out a flow cytometry-based analysis of post-HSCT immunologic reconstitution in patients with hematologic malignancies transplanted from donors harboring CH. We compared this data with those from a control cohort transplanted from donors without CH (No-CH), aiming at recognizing discrepancies supporting differential immune dynamics in CH-derived GVHD that might underlie tumor control. We were able to describe that mutations in specific genes drive differential immunologic recovery. DNMT3A-CH immune reconstitution led to T-cell functional state shifts towards higher Naïve and Central memory Treg subtypes, together with relative increase in CD8 T cells after 6 months vs. No-CH. PD1+ CD8 T cells in DNMT3A-CH were significantly expanded compared to No-CH cohort at all the studied time points. While TET2 and other mutations were associated with equivalent to higher B-cell count vs. No-CH, DNMT3A-CH showed inferior B-cell counts after 9 months. Within the whole CH cohort, we found significant increase in plasmacytoid dendritic cells compared to No-CH throughout the study monitoring. Taken together, these findings add translational support to the clinical evidence of higher cGVHD incidence in DNMT3A-CH and grant further investigation in the setting of post-HSCT CH in an effort to improve our knowledge of alloimmune tumor control.