Human leukocyte antigen (HLA) class I expression on Hodgkin–Reed–Sternberg cells is an EBV‐independent major determinant of microenvironment composition in classic Hodgkin lymphoma
Berit Müller‐Meinhard,
Nicole Seifert,
Johanna Grund,
Sarah Reinke,
Fatih Yalcin,
Helen Kaul,
Sven Borchmann,
Bastian vonTresckow,
Peter Borchmann,
Annette Plütschow,
Julia Richter,
Andreas Engert,
Michael Altenbuchinger,
Paul J. Bröckelmann,
Wolfram Klapper
Affiliations
Berit Müller‐Meinhard
Hematopathology Section and Lymph Node Registry, Department of Pathology University Hospital Schleswig‐Holstein Kiel Germany
Nicole Seifert
Department of Medical Bioinformatics University Medical Center Göttingen Göttingen Germany
Johanna Grund
Hematopathology Section and Lymph Node Registry, Department of Pathology University Hospital Schleswig‐Holstein Kiel Germany
Sarah Reinke
Hematopathology Section and Lymph Node Registry, Department of Pathology University Hospital Schleswig‐Holstein Kiel Germany
Fatih Yalcin
Hematopathology Section and Lymph Node Registry, Department of Pathology University Hospital Schleswig‐Holstein Kiel Germany
Helen Kaul
Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD) and German Hodgkin Study Group (GHSG), Faculty of Medicine and University Hospital of Cologne University of Cologne Cologne Germany
Sven Borchmann
Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD) and German Hodgkin Study Group (GHSG), Faculty of Medicine and University Hospital of Cologne University of Cologne Cologne Germany
Bastian vonTresckow
Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD) and German Hodgkin Study Group (GHSG), Faculty of Medicine and University Hospital of Cologne University of Cologne Cologne Germany
Peter Borchmann
Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD) and German Hodgkin Study Group (GHSG), Faculty of Medicine and University Hospital of Cologne University of Cologne Cologne Germany
Annette Plütschow
Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD) and German Hodgkin Study Group (GHSG), Faculty of Medicine and University Hospital of Cologne University of Cologne Cologne Germany
Julia Richter
Hematopathology Section and Lymph Node Registry, Department of Pathology University Hospital Schleswig‐Holstein Kiel Germany
Andreas Engert
Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD) and German Hodgkin Study Group (GHSG), Faculty of Medicine and University Hospital of Cologne University of Cologne Cologne Germany
Michael Altenbuchinger
Department of Medical Bioinformatics University Medical Center Göttingen Göttingen Germany
Paul J. Bröckelmann
Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD) and German Hodgkin Study Group (GHSG), Faculty of Medicine and University Hospital of Cologne University of Cologne Cologne Germany
Wolfram Klapper
Hematopathology Section and Lymph Node Registry, Department of Pathology University Hospital Schleswig‐Holstein Kiel Germany
Abstract Hodgkin–Reed–Sternberg cells (HRSCs) in classic Hodgkin Lymphoma (HL) frequently lack expression of human leukocyte antigen class I (HLA‐I), considered to hamper activation of cytotoxic T cells in the tumor microenvironment (TME). Here, we demonstrate HLA‐I expression on HRSCs to be a strong determinant of TME composition whereas expression of HLA‐II was associated with only minor differential gene expression in the TME. In HLA‐I‐positive HL the HRSC content and expression of CCL17/TARC in HRSCs are low, independent of the presence of Epstein–Barr virus in HRSCs. Additionally, HLA‐I‐positive HL shows a high content of CD8+ cytotoxic T cells. However, an increased expression of the inhibitory immune checkpoint LAG3 on CD8+ T cells in close proximity to HRSCs is observed. Suggesting interference with cytotoxic activity, we observed an absence of clonally expanded T cells in the TME. While HLA‐I‐positive HL is not associated with an unfavorable clinical course in our cohorts, they share features with the recently described H2 subtype of HL. Given the major differences in TME composition, immune checkpoint inhibitors may differ in their mechanism of action in HLA‐I‐positive compared to HLA‐I‐negative HL.
