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

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.

Genome-wide Screens Identify Lineage- and Tumor Specific-Genes Modulating MHC-I and MHC-II Immunosurveillance in Human Lymphomas

“…Most gene disruptions in our cellular models of DLBCL affect class I presentation similarly across different tumors, which is somewhat surprising given the heterogeneity across DLBCL (Nissen et al, 2019). However, we did observe genes having variable (and even opposing) effects in different tumors.…”

“…With frequent mutations, common localization in lymph nodes (a primary site of T cell activation), and constitutive expression of both MHC-I and MHC-II, DLBCLs are likely subjected to high levels of immunosurveillance. Indeed, immune evasion is common in DLBCL, with an estimated ~40-75% of biopsies showing aberrant MHC-I expression or localization (Challa-Malladi et al, 2011;Ennishi et al, 2019;Nijland et al, 2017), though genetic analyses have thus far been unable to explain all MHC-I low patient samples.…”

Checkpoint Inhibition in Non-Hodgkin's Lymphoma

“…It might be speculated that more efficacy will be observed when approaching a more naïve immune system and that the full potential has not yet been discovered; however, on the opposite, more side effects might be observed with earlier treatment. Finally, we are just beginning to understand the preexisting and developing immune escape mechanisms, which necessarily need to be explored to optimize the use of CIs [97].…”

Checkpoint-Inhibition bei Non-Hodgkin-Lymphom

“…Letztlich fangen wir gerade erst an, die vorhandenen und sich entwickelnden Immunevasionsmechanismen zu verstehen. Diese müssen jedoch noch eingehender untersucht werden, um CI optimal einsetzen zu können [97]. Buchstäblich Dutzende neuartige Wirkstoffe befinden sich derzeit kurz davor, in das Stadium der klinischen Entwicklung einzutreten [83] und die Zahl potenzieller Kombinationen übersteigt bei weitem jede realistische Möglichkeit, sie in prospektiven Studien näher zu untersuchen.…”