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. 2017 Mar 3;6(4):e1295202.
doi: 10.1080/2162402X.2017.1295202. eCollection 2017.

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

Marcel Nijland  1 , Rianne N Veenstra  2 , Lydia Visser  2 , Chuanhui Xu  2 , Kushi Kushekhar  2 , Gustaaf W van Imhoff  1 , Philip M Kluin  2 , Anke van den Berg  2 , Arjan Diepstra  2
Affiliations

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

Marcel Nijland et al. Oncoimmunology. .

Abstract

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.

Keywords: Diffuse large B-cell lymphoma; Epstein barr virus; Hodgkin lymphoma; human leukocyte antigen; immune checkpoint inhibitor; immune evasion; major histocompatibility complex; primary central nervous system lymphoma; therapy response.

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Figures

Figure 1.
Figure 1.
Immunohistochemical staining patterns in formalin fixed paraffin embedded classical Hodgkin lymphoma tissue for HLA class I, B2M and HLA class II. (A and B) negative and positive membranous staining for HLA class I heavy chains. (C and D) negative and positive membranous staining for B2M. (E and F) negative and positive membranous staining for HLA class II. 40x.
Figure 2.
Figure 2.
CLIP and HLA-DM immunohistochemistry in frozen classical Hodgkin lymphoma tissue from two representative patients. (A) aberrant membranous CLIP staining in (B) the absence of HLA-DM. (C) normal absence of membranous CLIP staining in (D) presence of cytoplasmic HLA-DM staining. Circles indicate tumor cells. 40x.
Figure 3.
Figure 3.
Immunohistochemical staining patterns in formalin fixed paraffin embedded diffuse large B-cell lymphoma tissue for HLA class I, B2M, HLA class II and HLA-DM. (A and B) negative and positive membranous staining for HLA class I heavy chains. (C and D) negative and positive membranous staining for B2M. (E and F) negative and positive membranous staining for HLA class II. (G and H) negative and positive cytoplasmic staining for HLA-DM. 40x.
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