Page 24 - Haematologica August 2018

M. de Charette et al.
taneous lymphoid malignancies in mice with TRAIL defi- ciency.80 Loss of TRAIL receptor was found in 6.8% of NHL.81 It is mainly caused by mutations of TRAIL death domain on chromosome 8p21.3 but may also occur at the transcriptional level by mutation of p53.82 Mutations of TRAIL receptor are found in 26% of MCL (55% of leukemic MCL vs. 19% of nodal MCL) and have a more aggressive phenotype.83
Inhibition of the stress-induced intrinsic pathway: BCL-2 overex- pression
BCL-2 family molecules are crucial regulators of the intrinsic pathway of mitochondrial apoptosis.84 BCL-2 itself is an anti-apoptotic protein but other members of the BCL-2 family are pro-apoptotic.
BCL-2 is one of most commonly mutated genes in NHL, notably in DLBCL (37% of cases, particularly in GC sub- type) and FL (54% of cases),85-87 whereas it is a rare event in peripheral T-cell lymphomas, MCL and PMBL.86
The t(14;18), present in almost all FL45 and 34% of GC- DLBCL88 (vs. 17% of non-GC DLBCL), juxtaposes the BCL-2 gene and the enhancer of the heavy chain immunoglobulin. Thus, it induces a constitutive overex- pression of BCL-2 and exposes BCL-2 oncogene to somat- ic hyper-mutations in the GC.84 Other mechanisms may explain genetic variations of the BCL-2 gene in t(14;18) negative DLBCL.84
In DLBCL, BCL-2 expression (but not mutation nor translocation) were historically associated with a worse prognosis but this negative impact seems to be overcome by the addition of rituximab to CHOP chemotherapy.86,89,90 Nevertheless, BCL-2 protein expression remains the strongest independent prognostic factor in primary cuta- neous DLBCL.91 In FL, Correia et al. found that the pres- ence of BCL-2 mutation at diagnosis was an independent risk factor of transformation and death, but patients were mostly treated without rituximab.92 This observation was not confirmed in another study in which FL patients were treated with a rituximab-containing regimen.87
Inhibition / killing of immune cells
PD-L1/L2 expression
PD-L1 and PD-L2 are members of the CD28 family and inhibit T cells through ligation to PD-1 receptor.56 Most FL contain a rich immune infiltrate of PD1+ cells, mostly in the inter-follicular areas, but tumor cells do not express PD-L1 (PD-L2 is weakly expressed in some rare tumor cells).52 In contrast, DLBCL often express PD-L1 and PD-L2 on tumor cells and in their microenvironment.52 PD-L1 and PD-L2 are more frequently expressed on tumor cells of ABC-DLBCL (36% and 60%, respectively) than GC- DLBCL (4% and 26%, respectively).93 PD-L1 is also fre- quently expressed on tumor cells of PMBL (71% of cases)94 and HL (97% of cases).14 In immune-privileged lym- phomas, level of PD-L1 protein expression is unknown in PTL and reported in a small study of PCNS lymphomas.95 The mechanisms responsible for PD-L1 and/or PD-L2 overexpression include: i) genetic alteration in 9p24; and ii) Epstein-Barr virus (EBV) infection. In the first case, the 9p24 amplicon contains the PD-L1 and PD-L2 genes that are directly amplified and over-expressed. It also contains the JAK2 gene that, indirectly, induces the transcription of
the PD-L1 and PD-L2 genes. 9p24 alterations are found in all cases of HL,14 in most cases of PMBL (9p24 amplifica- tion in 63% of cases and translocation in 20% of cases),96,97 in 54% of PTL, and 52% of PCNSL (mainly due to copy number gain, whereas translocations are rare),98 and in 19% of DLBCL (mainly due to copy number gains) partic- ularly in the non-GC subset.99 Structural variations dis- rupting the 3’ region of the PD-L1 gene are also implicated in 8% of DLBCL.100 Notably, immunoglobulin locus and CIITA are common partners of PD-L1 translocation.42,98,99 Finally, EBV infection (which is present in approx. 40% of HL tumors) also induces PD-L1 expression via the viral protein LMP1.101
PD-L1 expression in the tumor is an adverse prognostic factor for HL,14 PMBL,94 and DLBCL.93 Soluble PD-L1, although not correlated with PD-L1 expression by the tumor, is also associated with a poor prognosis in DLBCL.102,103 In these studies, high level of PD-L1 was asso- ciated with the clinical and histological aggressiveness of the disease.14,52,93,102
HLA-Gexpression
HLA-G is a non-classical MHC-I molecule transcribed in membrane-bound or soluble (sHLA-G) isoforms. HLA-G binds to the inhibitory receptors ILT2 (on lymphoid cells, including B cells, and myeloid cells) and ILT4 (on myeloid cells). HLA-G also binds to CD8 co-receptor and induces FAS-mediated apoptosis of T and NK cells.104
HLA-G is expressed in 24% of DLBCL105 and 67% of cHL (on RS) at a higher level than healthy controls.73,106 In HL, HLA-G expression is associated with the loss of MHC-I on RS and the absence of EBV.107
sHLA-G is increased in lymphoproliferative disorders and contributes to immune escape.108,109 Indeed, sHLA-G purified from plasma of patients with lymphoproliferative disorders inhibits T-cell proliferation in vitro.108 However, there is no correlation between the level of sHLA-G and clinical or pathological characteristics of the disease108 or its prognosis.110
Thus, HLA-G may have ambivalent effects in lym- phoma: on one hand, sHLA-G may inhibit the prolifera- tion of tumor B cells through ILT2 receptor whereas, on the other hand, HLA-G expressed in the tumor may pro- mote immune escape by inhibiting NK and CTL.104
CD47 expression
CD47, the expression of which is ubiquitous, interacts with the inhibitory receptor SIRPa expressed by myeloid cells and macrophages. CD47-SIRPa interaction delivers a “don’t eat me” signal to the phagocytic cells which prevents phagocytosis.111 Thus, CD47 may lead to immune evasion in two ways: i) by inhibiting phagocytosis;112,113 and ii) by inhibiting cross-presentation by dendritic cells (DC).114
In NHL, CD47 is expressed at a higher level on tumor B cells compared to normal B cells.112 Additionally, CD47 expression is increased on lymphoma cells circulating in the blood compared to lymphoma cells in lymph nodes supporting the role of CD47 in lymphoma dissemina- tion.113 Finally, high expression of CD47 is associated with poor prognosis in DLBCL and MCL.112
FASL expression
Tumor cells may also “counter-attack” immune effector cells by expressing FASL in order to kill them.115 FASL was found to be strongly expressed in aggressive B-cell lym-
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