Page 21 - Haematologica August 2018

Immune escape mechanisms in lymphoma
these immune escape mechanisms may be used to deter- mine the optimal immunotherapy for patients with lym- phoma.
How lymphoma may hide from the immune system
In order to evade immune eradication, tumor cells may first become “invisible”. This can be achieved by the loss or downregulation of molecules involved in antigen pres- entation (MHC), co-stimulation (CD80, CD86), and/or adhesion (CD54),8 thereby preventing their recognition by the immune system.
Two types of mechanisms may be responsible for the loss of these molecules: i) “hard lesions” which consist of irreversible genetic alterations of the gene of interest or genes implicated in their transcriptional regulation; and ii) “soft lesions” which are reversible epigenetic changes that repress gene expression9 (Figure 1, "hide").
Prevention of antigen presentation
MHC-I loss/downregulation
Loss of MHC-I at the surface of lymphoma cells (total loss or miss-localization) occurs in 55-75% of diffuse large B-cell lymphoma (DLBCL)10,11 and 63% of Hodgkin lym- phomas (HL).11 Most frequently, this results from mutations of the Beta2-microglobulin (b2M) gene which occurs in 29% of DLBCL,10 50% of primary mediastinal B-cell lym- phoma (PMBCL),12 and at least 50% of classical HL (cHL).13 In immune-privileged lymphomas, MHC-I loss was found in 18% of primary central nervous system lymphomas (PCNSL) but not in primary testicular lymphomas (PTL).11 In HL, MHC loss is preferentially observed in EBV-negative rather than in EBV-positive HL (83% vs. 27%).11 Patients whose Reed Stenberg cells (RS) are negative for MHC-I or b2M have a shorter progression-free survival (PFS).14 Interestingly, 9p24.1 amplification (leading to PD-L1 over- expression, as discussed below) adversely impacts survival only in HL patients in whom RS have lost MHC-I.15 Loss of MHC-I is also observed in 30% of Burkitt lymphomas (BL) and 20% of follicular lymphoma (FL)16 with rare b2M muta- tions.17 In FL, the frequency of b2M mutations is higher after histological transformation18 and is associated with a lower infiltration of the tumor by CD8 T cells.19
Other irreversible mechanisms leading to MHC-I loss include alterations in MHC-I gene.16,20 Unlike non-hemato- logic cancers, epigenetic mechanisms do not seem to be frequently responsible for MHC-I loss/downregulation in lymphoma.7
Importantly, natural killer (NK) cells are activated in the absence of MHC-I and in the presence of CD58 (which stimulates NK cells through CD2). Interestingly, 67% of DLBCL lack CD58 surface expression, and 61% lack both CD58 and MHC-I expression, thereby preventing NK-cell activation.10 Of note, genetic alterations of CD58 are also found in transformed FL but not in FL.18 Genetic lesions disrupting the CD58 gene have been found only in 10- 21% of DLBCLs, suggesting alternative mechanisms.10,21,22
MHC- II loss/downregulation
Transcriptional regulation
Expression of MHC-II is regulated, through epigenetic mechanisms. CREBBP regulates CIITA by catalyzing
H3K27 acetylation at its promoter/enhancer in normal GC B cells and lymphoma cell lines.23-25 CREBBP may undergo loss-of-function mutation in the histone acetyl transferase domain. Thus, in FL and DLBCL, mutations of CREBBP prevent CIITA transcription, which in turn prevent MHC- II transcription.
HLA-DR expression is lost in 20% of DLBCL26 and is associated with a reduced T-cell infiltrate within the tumor27 and a poor outcome.27,28 Moreover, 19% of DLBCL have MHC-II intra-cytoplasmic aberrant localization which is associated with a worse outcome. This mislocal- ization is preferentially seen in BCL-2 and c-MYC double expresser lymphomas. Of note, c-MYC down-regulates enzymes implicated in the antigen presentation machinery (cf 2.1.3).29 The mechanisms of MHC-II downregulation remain incompletely understood but seem to occur at tran- scriptional level independently of genetic lesions on MHC- II gene.30 Indeed, genes implicated in epigenetic regulation, including HMTs and HATs, are the most frequently altered genes in DLBCL (approx. 50% of GC-DLBCL and 30% of ABC-DLBCL).31 Moreover, DLBCL frequently harbor inac- tivating mutations of CREBP (19% of all DLBCL, 31% of GC-DLBCL and 6% of ABC-DLBCL)12 and CIITA (10% of DLBCL).12 CIITA is a target of somatic hypermutation (SHM) caused by AID.12 Finally, expression of CIITA and CREBP may be repressed through epigenetic silencing (i.e. independent of genetic alterations). Reduced expression of CIITA and CREBP is frequently found in DLBCL, leading to MHC-II downregulation and poor outcome.32-35 In some cases, MHC-II may be restored by lifting the repression of CIITA with HDAC inhibitors.33 MHC-II downregulation in DLBCL may also result from an overexpression of the tran- scription factor FOXP1 through a mechanism which, although not clearly elucidated, seems to be independent of CIITA.36 FOXP1 expression is associated with the non- GC phenotype (48% of GC-DLBCL vs. 71% of non-GC- DLBCL)37 and a poor prognosis.38 The underlying mecha- nisms responsible for FOXP1 overexpression remain large- ly unknown. Genetic alterations on chromosome 3p lead- ing to FOXP1 overexpression are found in a small subset of DLBCL.38 FOXP1 translocations are found in 5% of DLBCL and are associated with extra-nodal localizations and high proliferative index.39 Bea et al. also reported 15% of trisomy 3 and 31% of copy number gains of the chromosome 3p in ABC-DLBCL (versus 1% in GC-DLBCL), associated with MHC-II downregulation.40
In PMBCL, MHC-II downregulation also occurs at the transcriptional level and CIITA alterations is the most common mechanism:41 CIITA breaks are found in 38-56% of PMBCL and correlate with poor outcome;12,42 CREBP mutations are present in 11% of cases12 and abnormalities on chromosome 3 can be found, although rarely.40 However, loss of expression of MHC-II is found only in 12% of PMBCL.43 This is associated with poor survival.43
In FL, there is no evidence for mutation in MHC-II genes17 but CREBBP is mutated in 32-68% of cases17,34 and CIITA in 35%44 suggesting a downregulation at the tran- scriptional level. Furthermore, CREBBP mutation is an early event and a driver mutation in FL development.45
In HL, lack of MHC-II on RS occurs in 41% of cases and represents an independent prognosis factor.46 In 37.2% of cases, RS show aberrant localization in their cytoplasm.46 The mechanisms responsible for MHC-II loss in HL is not completely known but genomic CIITA break is found in 15% of HL42 and FOXP1 is not implicated.47
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