Skip to main content
. 2023 Nov 11;22:180. doi: 10.1186/s12943-023-01889-6

Table 1.

Checkpoints (potentially) involved in AML relapse after allo-HCT

Checkpoint Name Expression Impact on immune system regarding immune evasion (Potential) Therapeutic intervention Role in context of allo-HCT
PD-1 (CD279) Programmed cell death protein 1 T-cells, B cells, NK-cells Co-inhibitory signals, T cell exhaustion, Treg recruitment PD-1 antibodies (f.e. Nivolumab, Pembrolizumab) [7375] Association between high PD-1 expression and leukemia relapse [54, 55]
PD-L1 (CD274) Programmed cell death 1 ligand 1 AML blasts Co-inhibitory signals, T-cell exhaustion, Treg recruitment PD-L1 antibodies [76], silencing of PD-L1 by application of specific siRNA [77] Highly upregulated in cases of relapse [17, 45]
TIM-3 T-cell immunoglobulin and mucin-domain containing-3 AML blasts, T-cells, Tregs, NK-cells Overexpression in AML on various cell types; increased levels in the plasma together with soluble TIM-3 lead to T-cell exhaustion and impaired NK-cell function TIM-3 blockade [78], CAR-T-cells targeting TIM-3 [79] Increased expression on CD8+ T-cells of relapsing patients [47, 54]
Gal-9 Galectin-9 T-cells, secreted by AML cells Binds on TIM-3 and leads to IDO1 production; results in T-cell exhaustion and NK-cell dysfunction (see TIM-3) Gal9 antibodies (shown to promote T-cell mediated killing of tumor cells, but not for AML so far) [80] Unclear, may be involved in the TIM-3 immune escape mechanism
CTLA-4 cytotoxic T-lymphocyte-associated Protein 4

T-cells /Tregs

AML blasts

Upregulation leads to T-cell inhibition and T-cell exhaustion CLTA-4 antibody [81] Increased levels in relapsing patients [47, 82]
CD80 CTLA-4 Counter-Receptor B7.1/ T-Lymphocyte Activation Antigen CD80 Antigen presenting cells (APCs), AML blasts Provides costimulatory signal to T-cells (activation marker together with CD86) - upregulated in cases of relapse [17]; high expression correlates with low relapse-free survival [83]
TIGIT T-cell Immunoreceptor With Ig And ITIM Domains T-cells, Tregs, NK-cells Inhibits T-cell effector functions by binding CD155 or CD112, augments immunosuppressive function of Tregs TIGIT blockade [61] higher expressed in the BM of relapsed AML patients after allo-HCT [55, 58, 72]
CD155 (PVR) Poliovirus receptor, ligand for TIGIT DCs, macrophages, T-cells, B cells, tumor cells (AML) Inhibitory T-cell ligand; CD155-TIGIT pathway suppresses immune responses by secretion of IL-10 and reduced IL-12; induces a tolerogenic phenotype in T-cells, decreases NK-cell mediated tumor reactivity PVR/PVRL2 antibodies [84]; Downregulation by FLT3-inhibition (FLT3 inhibitors) [85] Potentially involved in immune escape of AML [62]
CD112 (PVRL2) poliovirus receptor related 2, ligand for TIGIT Tumor cells (AML) CD112-TIGIT interaction leads to immune suppression PVR/PVRL2 antibodies [84]; Downregulation by FLT3-inhibition (FLT3 inhibitors) [85] upregulated in cases of relapse [17]
CD47 CD47 molecule (macrophage immune checkpoint) LSC Increased expression inhibits phagocytosis of leukemia cells Humanized anti-CD47 [67, 86, 87] highly expressed on LSCs, potentially involved in relapse of AML [63]
CD200 CD200 molecule LSC Overexpression results in immunosuppression of and impaired metabolic function of T-cells CD200 antibody [71] High risk of relapse for CD200+ AML patients [6870]
KLRG-1 Killer Cell Lectin Like Receptor G1 Effector memory CD8 T-cells and NK-cells Co-inhibitory checkpoint KLRG-1 blockade (but not for AML so far) [88] increased co-expression of KLRG-1 together with PD-1 and TIGIT during relapse after allo-HCT [72]
LAG-3 Lymphocyte-activation gene 3 T-cells, NK-cells, plasmacytoid DCs co-inhibitory receptor, upregulated in AML LAG-3 blockade (NCT04913922, AML patients) Potential role in immune escape [89], but exact role unclear
OX40 (CD134) Tumor necrosis factor receptor superfamily, member 4 T-cells, Tregs OX40 recepter interaction with its ligand OX40L leads to a costimulatory signal for T-cell proliferation OX40 agonist monoclonal antibody [90] OX40 positive T-cells were more frequent in AML than in healthy individuals [45]; high expression of OX40 associated with poor survival [91]; OX40 overexpression in relapsed AML, but potential role in immune escape unclear [92]
VISTA V-domain Ig suppressor of T-cell activation Neutrophils, monocytes, macrophages, DCs, T-cells, Tregs, tumor cells Induces an immunosuppressive environment, inhibitory towards T-cells VISTA inhibitors (tested in clinical trials, but not for AML) [93] VISTA expression levels at baseline correlated with disease recurrence; relapse after chemotherapy within 2 years from diagnosis had increased VISTA expression in leukemia and T-cells [55, 72, 94] role regarding relapse after allo-HCT still unclear
B7-H3 (CD276) B7 homolog 3 protein AML blasts from patients with monocytic AML Attenuates cytotoxicity of NK-cells; stimulatory effect on Cd8 + cytolytic T-cell activity in AML; in contrast to this: B7-H3 reduces T-cell mediated Interferon release (exact role unclear) B/-H3 targeted CAR T-cells; monoclonal antibodies [95] upregulated in cases of relapse [17, 55, 72], high expression associated with poor prognosis
B7-H4 V-set domain-containing T-cell activation inhibitor 1 TAMs, antigen presenting cells (APCs) T-cell coinhibitory molecule; negatively influences T-cell immune responses by binding on activated T-cells Anti-B7-H4 [96] (not for AML so far) Promotes immune escape potentially also in AML; exact role in AML relapse unclear [55, 72]
LILRB4 leukocyte immunoglobulin-like receptor-B 4 Highly expressed on monocytic AML cells (Leukemia blasts and LSCs); monocytes, macrophages, DCs and plasma cells inhibitory checkpoint receptor, results in T-cell suppression via Treg activation Anti-LILRB4 CAR T-cell therapy [97] Potentially involved in immune escape, but role is unclear so far