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Tumor immune escape in acute myeloid leukemia: Class II-associated invariant chain peptide expression as result of deficient antigen presentation.

van Luijn MM, Chamuleau ME, Ossenkoppele GJ, van de Loosdrecht AA, Marieke van Ham S - Oncoimmunology (2012)

Bottom Line: In this overview, we discuss the role of class II-associated invariant chain peptide (CLIP) in acute myeloid leukemia (AML), one of the few tumors expressing HLA class II.The clinical impact, function and regulation of CLIP expression on leukemic cells is addressed, indicating its potential as immunotherapeutic target in AML.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology; Cancer Center Amsterdam; VU Institute for Cancer and Immunology; VU University Medical Center; Amsterdam, The Netherlands ; Department of Immunopathology; Sanquin Research and Landsteiner Laboratory; Academic Medical Center; University of Amsterdam; Amsterdam, The Netherlands.

ABSTRACT
In this overview, we discuss the role of class II-associated invariant chain peptide (CLIP) in acute myeloid leukemia (AML), one of the few tumors expressing HLA class II. The clinical impact, function and regulation of CLIP expression on leukemic cells is addressed, indicating its potential as immunotherapeutic target in AML.

No MeSH data available.


Related in: MedlinePlus

The potential role of CLIP in AML immunopathogenesis and immunotherapy. Situations before and after immunotherapy in patients with AML are proposed: (A) Tumor immunity in untreated CLIP- AML; LAA-specific T cell priming and recognition are optimal due to enhanced endogenous LAA presentation by leukemic cells. (B) Tumor immune escape in untreated CLIP+ AML; leukemia-specific T cell priming as well as recognition are hampered because of inhibition of DC function and low immunogenicity by CLIP+ leukemic cells. (C) Tumor immune escape in treated CLIP+ AML; although priming of leukemia-specific T cells is resolved by DC vaccination or T cell transfer, leukemic cells still escape their recognition by expressing CLIP. (D) Tumor immunity in treated CLIP+ AML; by using DC vaccination or T cell transfer in combination with in vivo immunomodulatory drugs, both T cell priming and recognition are targeted, which might induce a potent immune response against leukemic cells.
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Figure 1: The potential role of CLIP in AML immunopathogenesis and immunotherapy. Situations before and after immunotherapy in patients with AML are proposed: (A) Tumor immunity in untreated CLIP- AML; LAA-specific T cell priming and recognition are optimal due to enhanced endogenous LAA presentation by leukemic cells. (B) Tumor immune escape in untreated CLIP+ AML; leukemia-specific T cell priming as well as recognition are hampered because of inhibition of DC function and low immunogenicity by CLIP+ leukemic cells. (C) Tumor immune escape in treated CLIP+ AML; although priming of leukemia-specific T cells is resolved by DC vaccination or T cell transfer, leukemic cells still escape their recognition by expressing CLIP. (D) Tumor immunity in treated CLIP+ AML; by using DC vaccination or T cell transfer in combination with in vivo immunomodulatory drugs, both T cell priming and recognition are targeted, which might induce a potent immune response against leukemic cells.

Mentions: In Figure 1, a model is illustrated to show the potential influence of CLIP expression by leukemic cells on AML immunopathogenesis and on currently developed immunotherapeutic approaches to introduce anti-leukemic T cell immunity in AML, including dendritic cell (DC) vaccination and adoptive T cell transfer.7,8 In patients with CLIP- AML, leukemic cells should be well-recognized by presenting leukemia-associated antigens (LAAs) to CD4+ T cells or CTLs (Fig. 1A). This then initiates a potential feed-forward loop wherein exogenous antigens are internalized by DCs and presented for priming of leukemia-specific T cells. Only leukemia-specific priming of T cells might be suboptimal in these patients, which makes for example vaccination with LAA-loaded DCs a potential treatment option. However, in CLIP+ AML, CLIP on leukemic cells indicates deficient presentation of endogenous LAAs. This can put the feed-forward loop on hold, either directly by preventing their detection and eradication by T cells, or indirectly by creating an immunosuppressive environment that causes DC or T cell inactivation (Fig. 1B). Administration of ex vivo generated LAA-loaded DC vaccines or leukemia-specific T cells to these patients may establish LAA presentation to stimulate T cell priming.9 Still, it does not deal with CLIP expressed by leukemic cells that results in low immunogenicity and direct impairment of T cells (Fig. 1C). To circumvent this, additional immunotherapeutic strategies need to be included in current protocols that down-modulate CLIP in vivo (Fig. 1D). As a result, LAA presentation on HLA-I and HLA-II molecules might be simultaneously enhanced leading to effective T cell immunity against leukemic cells. One strategy may be to enhance the processing machinery of endogenous antigens, such as the stimulation of proteasomal and TAP function by histone deacetylase inhibitors (HDACi).10 The design of approaches that target the immune escape mechanisms used by leukemic cells to inhibit T cell activation could have great promise for future active immunotherapy in AML.


Tumor immune escape in acute myeloid leukemia: Class II-associated invariant chain peptide expression as result of deficient antigen presentation.

van Luijn MM, Chamuleau ME, Ossenkoppele GJ, van de Loosdrecht AA, Marieke van Ham S - Oncoimmunology (2012)

The potential role of CLIP in AML immunopathogenesis and immunotherapy. Situations before and after immunotherapy in patients with AML are proposed: (A) Tumor immunity in untreated CLIP- AML; LAA-specific T cell priming and recognition are optimal due to enhanced endogenous LAA presentation by leukemic cells. (B) Tumor immune escape in untreated CLIP+ AML; leukemia-specific T cell priming as well as recognition are hampered because of inhibition of DC function and low immunogenicity by CLIP+ leukemic cells. (C) Tumor immune escape in treated CLIP+ AML; although priming of leukemia-specific T cells is resolved by DC vaccination or T cell transfer, leukemic cells still escape their recognition by expressing CLIP. (D) Tumor immunity in treated CLIP+ AML; by using DC vaccination or T cell transfer in combination with in vivo immunomodulatory drugs, both T cell priming and recognition are targeted, which might induce a potent immune response against leukemic cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3376995&req=5

Figure 1: The potential role of CLIP in AML immunopathogenesis and immunotherapy. Situations before and after immunotherapy in patients with AML are proposed: (A) Tumor immunity in untreated CLIP- AML; LAA-specific T cell priming and recognition are optimal due to enhanced endogenous LAA presentation by leukemic cells. (B) Tumor immune escape in untreated CLIP+ AML; leukemia-specific T cell priming as well as recognition are hampered because of inhibition of DC function and low immunogenicity by CLIP+ leukemic cells. (C) Tumor immune escape in treated CLIP+ AML; although priming of leukemia-specific T cells is resolved by DC vaccination or T cell transfer, leukemic cells still escape their recognition by expressing CLIP. (D) Tumor immunity in treated CLIP+ AML; by using DC vaccination or T cell transfer in combination with in vivo immunomodulatory drugs, both T cell priming and recognition are targeted, which might induce a potent immune response against leukemic cells.
Mentions: In Figure 1, a model is illustrated to show the potential influence of CLIP expression by leukemic cells on AML immunopathogenesis and on currently developed immunotherapeutic approaches to introduce anti-leukemic T cell immunity in AML, including dendritic cell (DC) vaccination and adoptive T cell transfer.7,8 In patients with CLIP- AML, leukemic cells should be well-recognized by presenting leukemia-associated antigens (LAAs) to CD4+ T cells or CTLs (Fig. 1A). This then initiates a potential feed-forward loop wherein exogenous antigens are internalized by DCs and presented for priming of leukemia-specific T cells. Only leukemia-specific priming of T cells might be suboptimal in these patients, which makes for example vaccination with LAA-loaded DCs a potential treatment option. However, in CLIP+ AML, CLIP on leukemic cells indicates deficient presentation of endogenous LAAs. This can put the feed-forward loop on hold, either directly by preventing their detection and eradication by T cells, or indirectly by creating an immunosuppressive environment that causes DC or T cell inactivation (Fig. 1B). Administration of ex vivo generated LAA-loaded DC vaccines or leukemia-specific T cells to these patients may establish LAA presentation to stimulate T cell priming.9 Still, it does not deal with CLIP expressed by leukemic cells that results in low immunogenicity and direct impairment of T cells (Fig. 1C). To circumvent this, additional immunotherapeutic strategies need to be included in current protocols that down-modulate CLIP in vivo (Fig. 1D). As a result, LAA presentation on HLA-I and HLA-II molecules might be simultaneously enhanced leading to effective T cell immunity against leukemic cells. One strategy may be to enhance the processing machinery of endogenous antigens, such as the stimulation of proteasomal and TAP function by histone deacetylase inhibitors (HDACi).10 The design of approaches that target the immune escape mechanisms used by leukemic cells to inhibit T cell activation could have great promise for future active immunotherapy in AML.

Bottom Line: In this overview, we discuss the role of class II-associated invariant chain peptide (CLIP) in acute myeloid leukemia (AML), one of the few tumors expressing HLA class II.The clinical impact, function and regulation of CLIP expression on leukemic cells is addressed, indicating its potential as immunotherapeutic target in AML.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology; Cancer Center Amsterdam; VU Institute for Cancer and Immunology; VU University Medical Center; Amsterdam, The Netherlands ; Department of Immunopathology; Sanquin Research and Landsteiner Laboratory; Academic Medical Center; University of Amsterdam; Amsterdam, The Netherlands.

ABSTRACT
In this overview, we discuss the role of class II-associated invariant chain peptide (CLIP) in acute myeloid leukemia (AML), one of the few tumors expressing HLA class II. The clinical impact, function and regulation of CLIP expression on leukemic cells is addressed, indicating its potential as immunotherapeutic target in AML.

No MeSH data available.


Related in: MedlinePlus