HLA dependent immune escape mechanisms in B-cell lymphomas: Implications for immune checkpoint inhibitor therapy?

• Published in: Oncoimmunology Vol. 6; no. 4; p. e1295202
• Main Authors: Nijland, Marcel, Veenstra, Rianne N., Visser, Lydia, Xu, Chuanhui, Kushekhar, Kushi, van Imhoff, Gustaaf W., Kluin, Philip M., van den Berg, Anke, Diepstra, Arjan
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 03.04.2017; Taylor & Francis Group
• Subjects: Diffuse large B-cell lymphoma; Epstein barr virus; Hodgkin lymphoma; human leukocyte antigen; immune checkpoint inhibitor; immune evasion; major histocompatibility complex; Original Research; primary central nervous system lymphoma; therapy response; immune checkpoint inhibitor; immune evasion; human leukocyte antigen; therapy response; major histocompatibility complex; Epstein barr virus; primary central nervous system lymphoma; Diffuse large B-cell lymphoma; Hodgkin lymphoma
• ISSN: 2162-402X; 2162-4011; 2162-402X
• DOI: 10.1080/2162402X.2017.1295202

Antigen presentation by tumor cells in the context of Human Leukocyte Antigen (HLA) is generally considered to be a prerequisite for effective immune checkpoint inhibitor therapy. We evaluated cell surface HLA class I, HLA class II and cytoplasmic HLA-DM staining by immunohistochemistry (IHC) in 389 classical Hodgkin lymphomas (cHL), 22 nodular lymphocyte predominant Hodgkin lymphomas (NLPHL), 137 diffuse large B-cell lymphomas (DLBCL), 39 primary central nervous system lymphomas (PCNSL) and 19 testicular lymphomas. We describe a novel mechanism of immune escape in which loss of HLA-DM expression results in aberrant membranous invariant chain peptide (CLIP) expression in HLA class II cell surface positive lymphoma cells, preventing presentation of antigenic peptides. In HLA class II positive cases, HLA-DM expression was lost in 49% of cHL, 0% of NLPHL, 14% of DLBCL, 3% of PCNSL and 0% of testicular lymphomas. Considering HLA class I, HLA class II and HLA-DM together, 88% of cHL, 10% of NLPHL, 62% of DLBCL, 77% of PCNSL and 87% of testicular lymphoma cases had abnormal HLA expression patterns. In conclusion, an HLA expression pattern incompatible with normal antigen presentation is common in cHL, DLBCL, PCNSL and testicular lymphoma. Retention of CLIP in HLA class II caused by loss of HLA-DM is a novel immune escape mechanism, especially prevalent in cHL. Aberrant HLA expression should be taken into account when evaluating efficacy of checkpoint inhibitors in B-cell lymphomas.