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 | 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] | |
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 | 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] | |
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 | 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] | |
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 2Â 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 |