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Immune escape mechanisms in lymphoma
DLBCL patients treated with CHOP or rituximab-CHOP, Phipps-Yonas et al. identified lower GILT expression as an adverse prognostic factor for OS.55 Once formatted by GILT, peptides are loaded on MHC-II instead of CLIP frag- ment of invariant chain. This exchange is performed by HLA-DM. In absence of HLA-DM, antigens cannot be exposed and MHC-II present CLIP at the cell surface.11 HLA-DM is lost in 49% of cHL, 14% of DLBCL, and 2.9% of PTL and PCNSL.11
Prevention of co-stimulation: B7 molecule downregulation
CD80 and CD86 are members of the B7 co-stimulatory family and are expressed on professional APC, including B cells. They have a dual specificity: they can bind to the stimulatory receptor CD28 promoting T-cell activation and to the inhibitory receptor CTLA-4 (with a much high- er affinity than CD28) leading to T-cell inhibition.56
In B-cell lymphomas, CD80 and CD86 may be expressed on tumor cells and/or on cells from their microenvironment.57 CD80 is expressed in 97% of FL, 91% of marginal zone lymphomas (MZL), 90% of DLBCL, and 75% of mantle cell lymphomas (MCL).58 Interestingly, T and non-T cells present in the microenvi- ronment of these tumors also express CD80.58 Loss of CD86 was found to be associated with decreased TIL infiltration in DLBCL.59 However, the prognostic value of CD80 and CD86 expression in lymphoma remains unclear, maybe because of their dual activity.
Prevention of adhesion
Intercellular adhesion molecule 1 (ICAM-1 or CD54) plays a crucial role in cell-to-cell interaction, especially in the immune synapse and tumor cell adhesion and dissem- ination.8 Lower expression of CD54 compromises the interaction between tumor and immune cells. In DLBCL, lymphocyte infiltration is decreased in tumors which have lost CD54.59 However, in aggressive NHL, lower expres- sion of CD54 correlates with more advanced stage of the disease, higher bone marrow infiltration and worse prog- nosis.60
Expression of CD54 is lost in 50%60 of non-Hodgkin lymphomas (NHL), but only 7% in DLBCL.59
How lymphoma may defend itself against the immune system
Lymphoma cells may “defend” themselves to become resistant to immune eradication. This can be achieved in several ways: by becoming resistant to apoptosis and/or by expressing inhibitory ligands that deactivate immune cells (Figure 1, "defend").
Resistance to apoptosis
Three apoptopic pathways may induce cell death: i) the perforin/granzyme pathway which results from the release of cytotoxic granules from NK cells or CTL activat- ed through their TCR; ii) the extrinsic pathway, activated by T and NK cells through FAS or TRAIL death receptors; iii) the intrinsic pathway, involving BCL-2 family proteins and activated by intrinsic stress signals.61
By apoptopic gene profiling, Muris et al. identified two subsets of DLBCL with poor overall survival.62 The acti- vated apoptosis cascade group (mostly ABC-DLBCL) was
characterized by high expression level of many pro- and anti-apoptotic genes of the intrinsic pathway, suggesting that these lymphoma cells are “primed for death” and their survival depends on the high expression level of anti- apoptotic genes. The cellular cytotoxic response group was characterized by the expression of apoptosis-induc- ing effector molecules from CTL and NK cells (granzyme, TRAIL, FASL and other) and a high resistance to chemotherapy.63 The large immune cell infiltration in this subset suggests a selection of resistant lymphoma cells under the pressure of a strong cellular immune response.
Inhibition of granzyme
The protease inhibitor 9 (PI9) was found to inhibit granzyme B and therefore to protect against apoptosis.64 PI9 is expressed in DLBCL, BL and HL (in RS), but is seems to be rarely found in low-grade lymphomas.57 Of note, few studies have analyzed PI9 expression in B-cell lym- phomas and there is no evidence of relationship between PI9 expression and CTL infiltration or clinical outcome.65
To our knowledge, there is no mechanism of perforin inhibition in lymphoma.
Inactivation of death receptor extrinsic pathway: FAS/TRAIL-R
FAS (CD95) belongs to the TNF receptor family and lig- ation of FASL (CD95L) induces apoptosis through its intra- cellular death domain and caspase activation. This mech- anism plays a crucial role in affinity selection during the GC reaction.66 Immune cells also use this mechanism to kill cancer cells.67
In normal B cells, FAS is expressed on activated B cells from the GC and is absent in mantle zone or circulating B cells. CD95 is lost in 17% of FL68 and 27% of MALT lym- phomas.69 In DLBCL, CD95 is lost in 51% of extra-nodal cases69 but rarely in cutaneous cases.70 CD95 expression on lymphoma cells is associated with improved survival and response to R-CHOP therapy in DLBCL.69-72 In HL, CD95 is rarely lost.73
Mutations in the CD95 gene are more commonly found in post-GC lymphomas, including 20% of DLBCL, and 44% of extra-nodal lymphomas (all types).74,75 Surprisingly, although derived from GC, no mutation of CD95 were found in BL.75 CD95 mutations are rare in FL (6%) and in pre-GC lymphomas (<2%) such as MCL.74,75 Only 5% of HL are associated with FAS mutation in RS.73 Müschen et al. hypothesized that FAS mutations are mostly found in post-GC lymphomas because CD95 mutations are target errors in the SHM process during the GC reaction.74 However, FAS mutations do not share features of AID- mediated activity and their underlying mechanism remains unclear. In some cases, lymphoma cells express- ing CD95 are resistant to apoptosis, suggesting the exis- tence of other mechanisms. For instance, HL resist to FAS- induced apoptosis by expressing c-FLIP which is located at the cell membrane where it binds to the death domain of CD95.73 High levels of soluble CD95 are associated with poor outcome,76-78 supposedly because it binds to CD95L and prevents apoptosis. As discussed below, Galectin 3 also protects tumor cells from FAS-induced death.
TRAIL is also a member of TNF receptor family, which triggers the extrinsic apoptotic pathway after ligation to death receptors (TRAIL receptors 1 and 2). The role of TRAIL in B-cell lymphomagenesis has been suggested by the association between TRAIL polymorphisms and high- er risk of lymphoma79 and the rapid development of spon-
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