Immune landscape after allo-HSCT: TIGIT- and CD161-expressing CD4 T cells are associated with subsequent leukemia relapse

Abstract

Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is the most effective treatment for selected patients with acute myeloid leukemia (AML) and relies on a "graft-versus-leukemia" effect (GVL) where donor T lymphocytes mediate control of malignant cell growth. However, relapse remains the major cause of death after allo-HSCT. In various malignancies, several immunoregulatory mechanisms have been shown to restrain antitumor immunity, including ligand-mediated engagement of inhibitory receptors on effector cells, and induction of immunosuppressive cell-subsets such as regulatory T cells (Tregs) or myeloid-derived suppressor cells (MDSCs). While relapse after HSCT remains a major therapeutic challenge, immunoregulatory mechanisms involved in restraining the GVL effect need to be better deciphered in humans. We used mass cytometry to comprehensively characterize circulating leukocytes in two cohorts of patients after allo-HSCT. We first longitudinally assessed various immunoregulatory parameters highlighting specific trends, such as opposite dynamics between MDSCs and Tregs. More generally, the immune landscape was rather stable from month-3 to 6, while many variations occurred from month-6 to 12 post-HSCT. Comparison with healthy individuals revealed that profound alterations in the immune equilibrium persisted 1-year post-HSCT. Importantly, we found that high levels of TIGIT and CD161 expression on CD4 T cells at month 3 post-HSCT were distinct features significantly associated with subsequent AML relapse in a second cross sectional cohort. Altogether, these data provide global insights into the immunoregulatory landscape reconstitution following HSCT, and highlight non-canonical inhibitory receptors associated with relapse, which could open the path towards new prognostic tools or therapeutic targets to restore subverted anti-AML immunity.

Integrated bioinformatic analysis of mitochondrial metabolism-related genes in acute myeloid leukemia

“…By immune infiltration analysis, we found that the high-risk group showed higher immune scores, but increased ratio of gamma delta T cells, M2 macrophages, MDSCs and Tregs and increased expression of CTLA4 and IL2RA. In many cancers, immunoregulatory mechanisms have been proved to hamper antitumor immunotherapy, including ligand-mediated engagement of IRs on effector cells, such as CTLA4, and induction of immunosuppressive cell subsets, such as Tregs or MDSCs ( 78 – 80 ). IL2RA was demonstrated to be involved in inferior outcomes of AML patients ( 81 ).…”

Acute myeloid leukaemia relapse after allogeneic haematopoietic stem cell transplantation: Mechanistic diversity and therapeutic directions

“…27 TIGITmediated immune escape as a mechanism of post-HCT AML relapse was suspected as the TIGIT ligand is expressed on AML blasts, and the expression density was increased in post-HCT relapse samples. 27 Like clinical studies using anti-PD-1 and anti-CTLA-4 immunotherapy, further development using immune receptors and their ICM targets mentioned above are limited by concerns for GVHD exacerbation, and careful development to select responses on tumour without targeting healthy tissue by the alloreactive T-cells remains crucial. [27][28][29] Albeit less common altered expression in other immunerelated genes are implicated in post-HCT relapse.…”

“…27 Like clinical studies using anti-PD-1 and anti-CTLA-4 immunotherapy, further development using immune receptors and their ICM targets mentioned above are limited by concerns for GVHD exacerbation, and careful development to select responses on tumour without targeting healthy tissue by the alloreactive T-cells remains crucial. [27][28][29] Albeit less common altered expression in other immunerelated genes are implicated in post-HCT relapse. More commonly observed was significantly altered expression of immune-related genes post-HCT compared to diagnostic samples.…”

Dynamic comparison of early immune reactions and immune cell reconstitution after umbilical cord blood transplantation and peripheral blood stem cell transplantation

“…Immune reconstitution after HSCT is dominated by homeostatic peripheral expansion of the graft-derived cells during the initial stages post-transplantation ( 11 , 12 ). Differences in the immune reconstitution are expected between UCBT and PBSCT because they represent two diverse sources of HSCs and progenitor cells.…”