Role of Immune Escape Mechanisms in Hodgkin's Lymphoma Development and Progression: A Whole New World with Therapeutic Implications

Hindawi Publishing Corporation Clinical and Developmental Immunology Volume 2012, Article ID 756353, 24 pages doi:10.1155/2012/756353 Review Article Role of Immune Escape Mechanisms in Hodgkin’s Lymphoma Development and Progression: A Whole New World with Therapeutic Implications Luis de la Cruz-Merino,1 Marylène Lejeune,2 Esteban Nogales Fernández,1 Fernando Henao Carrasco,1 Ana Grueso López,1 Ana Illescas Vacas,3 Mariano Provencio Pulla,4 Cristina Callau,2 and Tomás Álvaro5 1 Clinical Oncology Department, Hospital Universitario Virgen Macarena, 41009 Sevilla, Spain 2 Molecular Biology and Research Section, Hospital de Tortosa Verge de la Cinta and IISPV, URV, 43201 Reus, Spain 3 Radiotherapy Department, Hospital Universitario Virgen Macarena, 41009 Sevilla, Spain 4 Clinical Oncology Department, Hospital Universitario Puerta de Hierro Majadahonda, 28222 Madrid, Spain 5 Pathology Department, Hospital de Tortosa Verge de la Cinta and IISPV, URV, 43201 Reus, Spain Correspondence should be addressed to Luis de la Cruz-Merino, Received 26 February 2012; Accepted 5 June 2012 Academic Editor: Keith Knutson Copyright © 2012 Luis de la Cruz-Merino et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hodgkin’s lymphoma represents one of the most frequent lymphoproliferative syndromes, especially in young population. Although HL is considered one of the most curable tumors, a sizeable fraction of patients recur after successful upfront treatment or, less commonly, are primarily resistant. This work tries to summarize the data on clinical, histological, pathological, and biological factors in HL, with special emphasis on the improvement of prognosis and their impact on therapeutical strategies. The recent advances in our understanding of HL biology and immunology show that infiltrated immune cells and cytokines in the tumoral microenvironment may play different functions that seem tightly related with clinical outcomes. Strategies aimed at interfering with the crosstalk between tumoral Reed-Sternberg cells and their cellular partners have been taken into account in the development of new immunotherapies that target different cell components of HL microenvironment. This new knowledge will probably translate into a change in the antineoplastic treatments in HL in the next future and hopefully will increase the curability rates of this disease. 1. Introduction The hallmarks of HL are mononuclear Hodgkin’s cells and multinuclear Reed-Sternberg (H/RS) cells, which usually account for only 1% of cells in tumor tissue. Evidence has accumulated that H/RS cells harbor clonally rearranged and somatically mutated immunoglobulin genes, indicating their derivation, in most cases, from germinal center (GC) B cells [1–3]. Some HL cases have been identified in which the H/RS is of T-cell origin but these are rare, accounting for 1-2% of cHL. Under normal conditions, GC B cells, that lack a functional high affinity antibody, undergo apoptosis in the germinal center. H/RS cells show a characteristically defective B-cell differentiation program, lose the capacity to express immunoglobulin, and, therefore, should die. However, H/RS cells escape apoptosis and instead proliferate, giving rise to the tumor and the immune response that characterizes [1– 3]. The presence of a characteristic inflammatory microenvironment is a fundamental component of the tumor mass and an essential pathogenetic factor in classical HL (cHL). It could supply the tumor cells with growth factors and could also inhibit antitumor immune responses. As the tumor cells and the reactive infiltrate grow up together, there is an extensive crosstalk between these two components mediated by cytokines and chemokines expressed by both cells. The most relevant mechanisms of immune escape are exerted by 2 neoplastic cells but also by specific immune cells polarized towards a Th2 phenotype in order to evade antitumor immunity. The pathogenetic role of Epstein-Barr virus (EBV) potentially based on cytotoxic T cells specifically directed towards EBV antigens also appears to influence the composition of the infiltrating immune cells population, which on the other side may have an impact on clinical presentation and outcome. The functional role of the microenvironment and the EBV in the pathophysiology and immune escape mechanisms of HL is an exciting new field of basic and translational research. Although chemotherapy and radiotherapy remain the cornerstone of HL treatment, up to 30% and 10% of patients will recur and die of HL in advanced and early disease, respectively. Therefore, current cancer research in HL aims to develop methods to increase the effectiveness of host antitumoral immune response, mainly with biologic therapies that use the body’s immune system, either directly or indirectly, to fight HL. 2. Microenvironment Composition in HL 2.1. Recruitment of HL Microenvironment. In most HL cases, H/RS cells represent the minority of the tumor burden and are dispersed among reactive elements comprising mixture of inflammatory cells, stromal cells, and a predominance of Th2 cells between the various subpopulations of lymphoid cells [4, 5]. Polarized Th1 and Th2 cells represent two subgroups of helper T cells that not only exhibit different functional properties but also show the preferential expression of some activation markers and distinct transcription factors. On the contrary to Th1 cells, the Th2 cells produce IL-4, IL-5, IL-10, and IL-13, which are responsible for strong antibody production and inhibition of several macrophage functions, thus providing phagocyte-independent protective responses. In such a setting, the “pressure” of the microenvironment over the neoplastic cells may be perceived as well as a strong reciprocal influence between H/RS cells and the diverse types of reactive cells. H/RS cells have a major role in the orchestration of the microenvironment milieu associated with HL. They can directly induce the recruitment of several immune cell types from the peripheral circulation and also trigger the local expansion of diverse cellular subsets. A whole plethora of soluble mediators synthesized by H/RS cells with chemotactic activity such as the cytokines and chemokines IL-5, IL-8, IL-9, CCL-5, and CCL-28 are involved in the recruitment of granulocytes, mast cells, and macrophages, whereas IL-7, CCL-5, CCL-17, CCL-20, and CCL-22 were effectors of lymphocyte recruitment and expansion [6]. Recruitment of infiltrating immune cells is also boosted by reactive cells themselves and particularly by macrophages and mast cells synthesizing CCL-3, CCL-4, and CCL-8 chemokines [6, 7]. Chemokine receptors, CXCR3, CXCR4, and CCR7, and adhesion molecules including CD62 ligand were found to be expressed on most T cells within HL tissues, while the corresponding li (...truncated)