High class II-associated invariant chain peptide expression on residual leukemic cells is associated with increased relapse risk in acute myeloid leukemia.

The presence of class II-associated invariant chain (CLIP) on leukemic cells is negatively associated with clinical outcome in untreated acute myeloid leukemia (AML). CLIP plays a role in the immune escape of leukemic cells, suggesting that it impairs the immunogenicity of minimal residual disease (MRD) cells causing a relapse. Here, we demonstrate that CLIP expression on leukemia-associated phenotype (LAP)-positive cells during follow-up is significantly correlated with a shortened relapse-free survival, even in those patients who are generally considered as MRD(low) (0.

Promiscuous binding of invariant chain-derived CLIP peptide to distinct HLA-I molecules revealed in leukemic cells.

Antigen presentation by HLA class I (HLA-I) and HLA class II (HLA-II) complexes is achieved by proteins that are specific for their respective processing pathway. The invariant chain (Ii)-derived peptide CLIP is required for HLA-II-mediated antigen presentation by stabilizing HLA-II molecules before antigen loading through transient and promiscuous binding to different HLA-II peptide grooves. Here, we demonstrate alternative binding of CLIP to surface HLA-I molecules on leukemic cells.

Absence of class II-associated invariant chain peptide on leukemic blasts of patients promotes activation of autologous leukemia-reactive CD4+ T cells.

Immune escape in cancer poses a substantial obstacle to successful cancer immunotherapy. Multiple defects in HLA class I antigen presentation exist in cancer that may contribute to immune escape, but less is known about roles for HLA class II antigen presentation. On class II(+) leukemic blasts, the presence of class II-associated invariant chain peptide (CLIP) is known to be correlated with poor survival in acute myeloid leukemia (AML).

High TRAIL-R3 expression on leukemic blasts is associated with poor outcome and induces apoptosis-resistance which can be overcome by targeting TRAIL-R2.

Activation of the TNF-related apoptosis-inducing ligand (TRAIL) pathway can induce apoptosis in a broad range of human cancer cells. Four membrane-bound receptors have been identified. TRAIL-R1 and TRAIL-R2 contain a functional death domain; TRAIL-R3 and TRAIL-R4 lack a functional death domain and function as decoy receptors.

Alternative Ii-independent antigen-processing pathway in leukemic blasts involves TAP-dependent peptide loading of HLA class II complexes.

During HLA class II synthesis in antigen-presenting cells, the invariant chain (Ii) not only stabilizes HLA class II complexes in the endoplasmic reticulum, but also mediates their transport to specialized lysosomal antigen-loading compartments termed MIICs. This study explores an alternative HLA class II presentation pathway in leukemic blasts that involves proteasome and transporter associated with antigen processing (TAP)-dependent peptide loading. Although HLA-DR did associate with Ii, Ii silencing in the human class II-associated invariant chain peptide (CLIP)-negative KG-1 myeloid leukemic cell line did not affect total and plasma membrane expression levels of HLA-DR, as determined by western blotting and flow cytometry.