PD‐L1 expression is low in large B‐cell lymphoma with MYC or double‐hit translocation

Abstract

In large B‐cell lymphoma (LBCL), MYC translocation and MYC/BCL2 or MYC/BCL6 double hit (DH) are associated with poor prognosis, and there is an unmet need for novel treatment targets in this patient group. Treatments targeting the PD‐L1/PD‐1 pathway are still poorly elucidated in LBCL. PD‐L1 expression might predict response to treatment targeting the PD‐L1/PD‐1 pathway. We therefore investigated the relationship between PD‐L1 protein and mRNA expression levels and MYC and DH translocation in LBCL. We detected MYC, BCL2, and BCL6 translocation by fluorescent in situ hybridization in tissue samples from 130 patients randomly selected from two cohorts of patients with LBCL: 49 patients with MYC translocation of whom 36 had DH and 81 without MYC translocation. PD‐L1 protein expression was detected by immunohistochemistry (IHC) in tissue samples from 77 patients and PD‐L1 mRNA expression by next‐generation RNA sequencing (NGS) in another 77 patients. Twenty‐four patients overlapped, ie, were analysed with both IHC and NGS. Nonparametric tests were performed to evaluate intergroup differences. PD‐L1 protein expression level was significantly lower in patients with MYC (n = 42, median = 3.3%, interquartile range [IQR] 0.0‐10.8) or DH translocations (n = 31, median = 3.3%, IQR 0.0‐10.0) compared with patients with no MYC (n = 35, median = 16.7%, IQR 3.3‐30.0) or no DH translocations (n = 46, 13.3%, IQR 2.5‐30.0), P = .004 and P ≤ .001, respectively. PD‐L1 mRNA expression was also significantly lower in patients with MYC or DH translocations, P = .001 and P = .006, respectively. Higher PD‐L1 protein and mRNA expression levels were associated with non–germinal centre (GC) type compared with germinal centre B‐cell (GCB)‐type diffuse LBCL (DLBCL), P = .004 and P = .002, respectively. In conclusion, we report an association between low PD‐L1 expression and MYC and DH translocation in patients with LBCL. Our findings may indicate that patients with MYC or DH translocation may benefit less from treatment with PD‐L1/PD‐1‐inhibitors compared with patients without these translocations. This should be evaluated in larger, prospective, consecutive trials.

Impact of MYC on Anti-Tumor Immune Responses in Aggressive B Cell Non-Hodgkin Lymphomas: Consequences for Cancer Immunotherapy

“…Programmed death-ligand 1 (PD-L1), also known as B7-H1 or CD274 , is a member of the B7 receptor family and the primary ligand for PD-1, one of the most important co-inhibitory molecules on T cells to regulate excessive T cell responses [ 61 ]. In DLBCL, high PD-L1 expression in tumor cells correlates with the non-germinal center B cell (non-GCB) subtype [ 62 , 63 , 64 , 65 , 66 , 67 , 68 ], inferior treatment outcome [ 63 , 66 ] and decreased progression free survival [ 66 ] and overall survival [ 62 , 63 , 65 , 68 ].…”

“…Since MYC and STAT1 can regulate their mutual expressions [ 78 , 79 ], it seemed possible that MYC inactivation increased STAT1, leading to increased PD-L1 expression [ 77 ]. Furthermore, two other cohorts of de novo and relapsed DLBCL patients reported a negative correlation between MYC and PD-L1 [ 63 , 64 ]. Finally, some other studies were not able to detect any correlation between MYC and PD-L1 at all in either DLBCL cell lines [ 80 ], nor in DLBCL patients [ 60 , 66 , 68 , 81 ].…”

Drug therapy for double-hit lymphoma

“…Pembrolizumab is currently FDA approved for R/R primary mediastinal large B-cell lymphoma (PMBCL) based on KEYNOTE-170/-013, but PMBCL typically has higher expression of PD-L1 compared with DLBCL 73,74. The clinical efficacy of PD-1 inhibition in DLBCL as a single agent is very low (ORR and CR rates at 10 and 3%, respectively), likely due to low PD-L1 expression (especially in DHL/THL) and/or low frequency of 9p24.1 genetic alterations 75,76…”

CD24 is a surrogate for ‘immune‐cold’ phenotype in aggressive large B‐cell lymphoma

“…HGBL with MYC and BCL2 and/or BCL6 gene rearrangement, mainly derived from germinal center B cells (GCB), was shown to have less T-cell infiltration and few alterations of inflammation-related NF-kB pathway genes [12]. Recently, rare expression of PD-L1/L2 in HGBL was reported [13,14]. These observations indicate that the difference between immunotherapy-sensitive and immunotherapy-resistant lymphoma depends not only on the intrinsic properties of tumor cells such as genetic alteration of lymphoma cells and cell-of-origin (COO), but also whether the TME is 'immune-hot' or 'immune-cold'.…”