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suppressive environment in several ways: i) it induces an exhausted phenotype in CTL (mostly on memory T cells) with a high PD-1 and TIM-3 expression;123 ii) it leads to FOXP3 expression, mostly in naïve T CD4+ cells123 and induces the differentiation of Treg; and iii) represses the expression of CD95, perforin, granzyme and cytokines.124 Because TGF-b suppresses lymphoma growth by inhibit- ing proliferation and apoptosis, lymphoma cells may first acquire resistance or aberrant response to TGF-b.124 This may be achieved by several mechanisms including down- regulation of TGF-b receptor on lymphoma cells125 through epigenetic mechanisms,126 abnormal signal trans- duction127 and expression of CD109, a negative regulator of TGF-b signaling.128 Thus, there is no clear prognostic impact of TGF-b in lymphoma.
IDO expression
IDO is an enzyme, expressed by lymphoma cells and cells from the microenvironment, which suppresses CTL and NK immune responses and induces Treg through
degradation of tryptophan. The most important metabo- lite of tryptophan is kynurenine which inhibits antigen specific proliferation and induces T-cell death.129
IDO protein is expressed in stromal cells of HL130 and approximately 30% of NHL express IDO, and intra- tumoral levels are significantly higher than in reactive lymph nodes.131-133 In DLBCL131-133 and HL,130,134 IDO activity is associated with a more aggressive disease and a worse outcome. Upregulation of IDO is associated with Treg infiltration in both DLBCL and HL.130,133
Galectins expression
Galectins (Gal) are key regulators of inflammation. These molecules act in the extra-cellular milieu by inter- acting with glycosylated receptors and, at the intra-cellular level, by modulating signalization and splicing.135 Among the 15 different galectins identified, types 1 and 3 have been implicated in lymphoma immune escape. Gal-1 is known to suppress Th1 responses and promote secretion of Th2 cytokines and expansion of Treg. Gal-1 is over-
Table 2. Strategies to reverse immune escape mechanisms in lymphoma.
Treg: regulatory T cells; mAb: monoclonal antibody; DC: dendritic cell. *No result available in lymphoma patients. #Pre-clinical data.
haematologica | 2018; 103(8)