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Tumormikromilieu im klassischen Hodgkin-Lymphom

Microenvironment in classical Hodgkin lymphoma

  • Schwerpunkt: Unser Immunsystem – der Staat im Staate
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Zusammenfassung

Das klassische Hodgkin-Lymphom (cHL) ist auf histologischer Ebene gekennzeichnet durch ein quantitativ dominierendes Begleitinfiltrat, das in Abhängigkeit vom histologischen Subtyp und EBV(Epstein-Barr-Virus)-Status eine unterschiedliche Zusammensetzung aufweist. Derzeitig gültige pathogenetische Konzepte postulieren, dass die malignen Zellen in Form der sogenannten Hodgkin- bzw. Reed-Sternberg(HRS)-Zellen eine dominante Rolle in der Rekrutierung verschiedener Immunzellen einnehmen, die wiederum zum Überleben der Tumorzellpopulation beitragen. Unterstützt wird diese Hypothese durch genetische Analysen, die entscheidend dazu beigetragen haben, relevante Mechanismen zu identifizieren, mithilfe derer sich die HRS-Zellen einer wirksamen Immunantwort entziehen können. Neben einer reduzierten bzw. defekten Antigenpräsentation bedingt durch strukturelle Chromosomenaberrationen und Mutationen in Komponenten bzw. Regulatoren der Haupthistokompatibilitätskomponenten Klasse I und II, kommen vor allem Kopienzahlzugewinne des 9p24.1-Lokus eine bedeutsame Rolle zu. Letztere resultieren zumeist in einer verstärkten Expression von Liganden des programmierten Zelltod-Proteins PD‑1, die durch die Interaktion mit diesem auf T‑Lymphozyten exprimierten Rezeptor zu einer Suppression der Immunantwort führen. Die Reversibilität dieser inhibitorischen Rezeptor-Liganden-Wechselwirkung wird klinisch in Form sog. Checkpoint-Inhibitoren genutzt, die bei Patienten mit cHL, insbesondere auch in der Rezidivsituation, mit im Vergleich zu vielen anderen Tumorentitäten imposanten Ansprechraten überzeugt haben. Ultimatives Ziel ist die Integration dieser Informationen in prognostische bzw. prädiktive Modelle, die eine rationale Risikostratifizierung und basierend darauf eine Selektion optimaler Therapieregime ermöglicht.

Abstract

Classical Hodgkin lymphoma (cHL) is histologically characterized by a quantitatively dominating immune cell infiltrate. Its composition differs depending on the histological subtype and EBV (Epstein-Barr-Virus) status. Current pathogenic concepts postulate that the malignant cells, the so-called Hodgkin and Reed-Sternberg (HRS) cells, act as master recruiters, thereby actively shaping the microenvironment to support their proliferation and outgrowth. This view on the pathogenesis of cHL is further solidified by genetic studies, which have identified important mechanisms by which the HRS cells are enabled to escape immune surveillance. Besides an insufficient antigen presentation mediated by mutations and structural chromosomal changes in key components or regulators of major histocompatibility class I and II molecules, copy number gains of the 9p24.1 genomic locus encompassing JAK2 and the ligands of the programmed cell death protein 1 (PD-1), PD-L1 and PD-L2, play an important role in the pathogenesis of this disease as the engagement of those ligands with their cognate receptor leads to suppression of the immune response. Of importance, the reversibility of this inhibitory receptor-ligand interaction is key to the clinical success that checkpoint inhibitors had and continue to have in cHL patients, especially in the relapse setting. In addition, comprehensive assessment of microenvironment composition, integration with results from genetic studies, and correlation with clinical outcomes have led to the development of prognostic models, which may assist in an improved risk stratification, informed selection of treatment regimens, and therefore better outcomes.

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  1. Institut für Humangenetik, Universitätsklinikum Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Deutschland

    Anja Mottok

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Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

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P. Möller, Ulm

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Mottok, A. Tumormikromilieu im klassischen Hodgkin-Lymphom. Pathologe 41, 254–260 (2020). https://doi.org/10.1007/s00292-020-00774-z

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