MHC class II molecules are able to present tumor antigens to CD4+ T cells which play in their turn an important role in orchestrating the anti-tumor immune response. MHC class II molecules are only able to present antigen when the antigen binding site has been liberated from CLIP, which is a remnant of the intracellular chaperone molecule called Invariant Chain. Impaired MHC class II antigen presentation by persistent expression of CLIP on the antigen binding site of > 35% of the leukemic myeloid cells at diagnosis of AML patients is correlated to shorter overall survival (

Chamuleau et al, Cancer Res. 2004; 64:5546–5550
). In this study, we investigated the CLIP expression on minimal residual disease (MRD) cells in the bone marrow of patients who achieved complete remission after chemotherapeutic treatment. Such expression may reveal the role of immune control in the outgrowth of MRD cells towards a relapse. The presence of MRD was measured by leukemia associated phenotype (LAP) expression (e.g. expression of the lymphoid cell marker CD7 or natural killer cell marker CD56 on myeloid blasts). Such aberrancies can be defined on AML blasts at diagnosis. At first, we established the percentage of MRD cells of 19 patients who remained in continuous complete remission (median follow up 44 months, range 7.4–109 months, sample taken at median 21 months after complete remission) and of 15 patients who relapsed soon after samples were taken (median time before relapse occurred: 5.9 months, range 1.4–20 months). The median frequency of MRD cells in relapsing patients was 0.1% (range 0.01 – 3.1%) compared to 0.02% (range 0.01–0.09%) in patients who remained in continuous remission. Differences were significant (p=0.017, Mann-Whitney U), in line with our previous finding that a high MRD cell frequency correlates with a high relapse rate (
N. Feller et al, Leukemia 2004, 18:1380–1390
). Furthermore, we established the CLIP expression on the CD34+ LAP+ cells of both groups. Patients that relapsed showed a significant higher median CLIP expression (69%, range 6–96%, SD 27) than the patients that remained in continuous complete remission (median CLIP expression of 31.6% (range 5–93%, SD 26)) p=0.012 (Mann-Whitney U). In a logistic regression analysis both parameters were independent factors for predicting relapse (p=0.014 for CLIP expression and p=0.035 for MRD frequency). In conclusion, the impaired immunogenicity of low frequency MRD cells in patients that are morphologically in complete remission seems to play an important role in the outgrowth of MRD to relapsing leukemia. Enhancing the immunogenicity of MRD cells by restoration of the MHC class II antigen presentation pathway could offer new possibilities for immune therapy of AML patients.

Topics:
neoplasm, residual, peptides, complete remission, leukemia, molecule, histocompatibility antigens class ii, antigens, cancer, cd56 antigens, disease remission

Disclosure: No relevant conflicts of interest to declare.

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2006, The American Society of Hematology
2006
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