Thesis Marvin van Luijn

On 15 February 2012 Marvin van Luijn defended his thesis 'Impaired Antigen Presentation as Immune Escape Mechanism in Acute Myeloid Leukemia' at the VU University Amsterdam.

Promotor: Prof GJ Ossenkoppele PhD
Co-promotores: AA van de Loosdrecht PhD and prof SM van Ham PhD

Summary

The human body is normally protected against uncontrolled growth of cancer cells by the immune system. Acute myeloid leukemia (AML) is a type of blood cell cancer in which myeloid cell differentiation is blocked, leading to an accumulation of immature abnormal cells (leukemic cells) in bone marrow and blood. Interestingly, leukemic cells can circulate in the blood of patients without being recognized by T cells, which are specialized in eradicating cancer cells. This thesis describes the research on the ability of leukemic cells to escape from T cell recognition and whether this contributes to the disease course of AML. The primary mechanism for T cell recognition of infected or cancer cells is antigen presentation; small non-self proteins (antigens) are presented on the cell surface by so-called HLA molecules, resulting in the recognition by and activation of T cells. The capability of leukemic cells to present antigens was studied with emphasis on a small self protein termed ‘CLIP’, which normally prevents antigen presentation. CLIP expression on leukemic cells of AML patients was shown to be associated with disease-free survival and predictive for disease recurrence after chemotherapeutic treatment. Furthermore, patient-derived cell cultures revealed that CLIP expression on leukemic cells strongly reduced activation and function of T cells. Also, evidence was found for new antigen presentation pathways that could explain the presence of CLIP on leukemic cells. These data indicate an important role of CLIP in immune escape of leukemic cells, which might provide novel insights into the development of AML immunotherapy.

Contents

PART I General introduction

Chapter 1

Introduction, scope and outline of the thesis
Parts of this chapter have been published in Immunotherapy 2010; 2(1):85-97.

PART II Dendritic cells as APCs in AML

Chapter 2

Recent advances in antigen-loaded dendritic cell-based strategies for treatment of minimal residual disease in acute myeloid leukemia. Immunotherapy 2010; 2(1):69-83 .

Chapter 3

Targeting Toll-like receptor 7/8 enhances uptake of apoptotic leukemic cells by monocyte-derived dendritic cells but interferes with subsequent cytokine-induced maturation. Cancer Immunol Immunother 2011; 60(1):37-47.

PART III Leukemic cells as APCs in AML

Chapter 4

Class II-associated invariant chain peptide down-modulation enhances the immunogenicity of myeloid leukemic blasts resulting in increased CD 4+ T cell responses.
Haematologica 2010; 95(3):485-96.

Chapter 5

Absence of class II-associated invariant chain peptide on leukemic blasts of patients promotes activation of autologous leukemiareactive CD 4+ T cells.
Cancer Res 2011; 71(7):2507-17.

Chapter 6

High class II-associated invariant chain peptide (CL IP) expression on residual leukemic cells is associated with increased relapse risk in acute myeloid leukemia.
Submitted for publication

Chapter 7

Alternative Ii-independent antigen processing pathway in leukemic blasts involves TAP -dependent peptide loading of HLA class II complexes.
Cancer Immunol Immunother 2010; 59(12):1825-38.

Chapter 8

Class II-associated invariant chain peptide expression represents a novel parameter for flow cytometric detection of acute promyelocytic leukemia.
Am J Pathol 2011; 179(5):2157-61.

Chapter 9

Promiscuous binding of invariant chain-derived CL IP peptide to distinct HLA -I molecules revealed in leukemic cells.
Submitted for publication.

PART IV Summarizing discussion

Chapter 10

Summary, discussion and future directions.
Parts of this chapter have been published in Immunotherapy 2010; 2(1):85-97 and Onco Immunol 2011; in press.