Absence of Class II–Associated Invariant Chain Peptide on Leukemic Blasts of Patients Promotes Activation of Autologous Leukemia-Reactive CD4+ T Cells

Abstract

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 þ 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). In this study, we evaluated the functional significance of CLIP expression on leukemic blasts of AML patients. CD4 repertoires) that were associated with better leukemia-specific reactivity than with CLIP þ leukemic blasts. Our findings offer a clinical rationale to downmodulate CLIP on leukemic blasts as a strategy to degrade immune escape and improve leukemia-specific T-cell immunity in AML patients. Cancer Res; 71(7); 2507-17. Ó2011 AACR.

HLA class II antigen-processing pathway in tumors: Molecular defects and clinical relevance

“…23,65,66 In contrast, some CLIP ¡ tumor cells were able to process li-independent endogeneous antigens generated by the proteasome for HLA class II-restricted presentation thereby activating TAA-specific CD4 C T cells. 23,67 Furthermore, it has recently been suggested that the different HLA class II phenotypes in tumors can be controlled at the post-transcriptional level, in particular by microRNAs (miRs). 42 Bioinformatic analyses have identified a number of miRs binding to the 3 0 -untranslated region (3 0 -UTR) of CIITA.…”

Class II–Associated Invariant Chain Peptide Expression Represents a Novel Parameter for Flow Cytometric Detection of Acute Promyelocytic Leukemia

“…A small remnant of this protein, the class II-associated invariant chain peptide (CLIP), can be presented by HLA-DR complexes on the surface of leukemic blasts, resulting in decreased immunogenicity. 15 Interestingly, in APL cases, we observed that CLIP was abundantly expressed at the surface of HLA-DR-negative leukemic promyelocytes. Here, we studied the application of the analysis of CLIP expression in the discrimination of HLA-DRnegative AML subgroups, including APL, by flow cytometry.…”

Class II-associated invariant chain peptide as predictive immune marker in minimal residual disease in acute myeloid leukemia

“…We have previously shown that leukemic cells expressing CLIP are poorly recognized by CD4C T helper cells. 5 Alternatively, we revealed that CLIP can also be presented by HLA class I, implicating that insufficient recognition by cytotoxic CD8C T cells might play a role as well. 6 Probably, genes regulating the antigen presentation pathway are impaired in leukemic cells, leading to increased expression of CLIP.…”

“…5 In our recent study, we assessed whether CLIP on residual leukemic cells could add to the prognostic value of MRD frequency for relapse risk. 7 The current cutoff for MRD positivity is 0.1%.…”