Abstract
ABSTRACTAntigen 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.
Highlights
In the past decade, cancer immunotherapy has made major advances by targeting a series of cell surface molecules known as immune checkpoints
As proper antigen presentation in the context of Human Leukocyte Antigen (HLA) is expected to be a prerequisite for the action of immune checkpoint inhibitors, we studied HLA expression in retrospective cohorts of B-cell lymphoma
We showed that only a minority of classical Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL), PNCSL and testicular lymphoma cases show HLA expression that is compatible with normal antigen presentation for both HLA class I and II
Summary
Cancer immunotherapy has made major advances by targeting a series of cell surface molecules known as immune checkpoints. The checkpoint molecules can repress the function of killer and pro-inflammatory lymphocytes. Checkpoint inhibitors are monoclonal antibodies (mAbs) that block these inhibitory receptors, thereby stimulating T-cells and generating an antitumor response.[1,2,3] B-cell lymphoma comprise a heterogeneous group of malignancies, which arise from malignant transformation of B-cells. The mAbs against programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) have shown substantial therapeutic activity in heavily treated classical Hodgkin lymphoma (cHL) and encouraging results in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) with overall response rates (ORR) of 87% and 36% respectively.[4,5,6,7,8] Despite these encouraging results, complete remissions are rare and it remains to be established which patients benefit most from checkpoint inhibition
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