Page 27 - Haematologica August 2018

Immune escape mechanisms in lymphoma
expressed in EBV-associated lymphoma cells and is associ- ated with an increased secretion of Th2 cytokines and infiltration by Tregs.135
Gal-3 can positively or negatively regulate T-cell sur- vival, cytokine profiles and DC function. Gal-3 protects tumor cells from death induced by FAS,136 possibly through interaction with CD45.137 Gal-3 is over-expressed in 66% of DLBCL136 (but not in BL nor in FL).
Cells
Regulatory T cells
Tregs, which are characterized by the expression of CD4, FOXP3 and CTLA-4, are responsible for the preven- tion of autoimmunity.138 Tregs suppress immune cells through direct contact-dependent mechanisms, including induction of effector cell death, and indirect mechanisms by secreting inhibitory cytokines (IL-10, TGF-b) or inter- fering with effector T-cell metabolism.138
Tregs are more numerous in lymphoma tumors than in reactive lymph nodes139 and in the blood of lymphoma patients compared to healthy controls or cured patients.139,140 Tregs are recruited by CCR4 ligands (notably in cutaneous DLBCL, HL and EBV-associated lym- phomas141) or converted from a conventional into a regula- tory phenotype within the tumor microenvironment by modulation of tryptophan catabolism. Interestingly, Liu et al. demonstrated that Tregs found within the tumor microenvironment of FL are highly clonal.142 In this study, the diversity of Treg TCR repertoire inversely correlated with the TCR repertoire of CD8 T cells, suggesting an antigen-specific suppression of CTL by Tregs. High level of circulating Tregs at diagnosis is an adverse prognostic factor in DLBCL and correlates with elevated LDH, advanced stage of the disease,139 and poor survival.138,143
Myeloid-derived suppressor cells
Myeloid-derived suppressor cells (MDSC) were recently described and remain poorly characterized. While their immunosuppressive properties are well established, only few mechanisms have been explored in lymphoma.144 Immunosuppressive functions of MDSC include: i) secre- tion of immunomodulatory factors and Treg expansion; ii) modulation of amino-acid metabolism and decrease of T- cell proliferation; iii) oxidative stress; iv) inhibition of T- or NK-cell viability and homing into the lymph nodes; and v) induction of T-cell apoptosis. In B-cell lymphoma, MDSC are involved in T-cell defect through PDL-1 expression, IL- 10 secretion, Treg expansion, and modulation of amino- acid metabolism.144 MDSC are increased in various B-cell lymphomas (including HL, DLBCL, FL) and correlate with poor prognosis.144,145
Macrophages
Macrophages are divided into M1 (pro-inflammatory, CD163-) and M2 (anti-inflammatory, CD163+) subsets. M2 macrophages are recruited into the tumor or differenced in situ (notably by IL-10) and promote tumor progression.146
In HL, a meta-analysis of 22 studies showed that a high density of CD68+/CD163+ macrophages was associated with poor survival.147 In DLBCL146 and MCL,148 CD163+ macrophages correlates with poor clinical outcome. In FL, a high density of CD68+ macrophages was associated with a poor prognosis in the pre-rituximab era while it was associated with a good prognosis in the post-ritux-
imab era.146 This may be due to the antitumor activity of macrophages through phagocytosis of rituximab-coated tumor B cells.149 This observation was further supported by the GELA-GOELAMS study showing that macrophages were associated with adverse outcome only in patients treated without rituximab while there was no difference in survival in patients treated with rituximab.150 Finally, macrophages may also promote immune evasion by expression of PDL-1.146
Immune escape mechanisms in T-cell lymphomas
Mechanisms of immune evasion in T-cell lymphomas are less well characterized. Best described mechanisms result from resistance to apoptosis and from PD-L1 expression.
PI9 granzyme inhibitor is expressed in 21% of anaplas- tic large cell lymphoma (ALCL), 27% of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), 80% of NK-/T-cell nasal type lymphoma (ENKTL), and 89% of enteropathy-type NHL.63 A defect in the extrinsic apopto- sis (i.e. FAS) pathway is observed in many T-cell lym- phomas which may be caused by three distinct mecha- nisms: i) FAS mutations, which are present in 50% of ENKTL151 and in some cases of MF (<20% of cases);152 ii) decreased expression of FAS through epigenetic mecha- nisms such as promoter methylation (45% of Sezary Syndrome) or splicing (43% of MF, 50% of CD30- CTCL);152 iii) expression of c-FLIP inhibitory protein, which is seen in 90% of ALCL153 (although the underlying mechanism is not completely elucidated).
Both PD1 and PD-L1 may be expressed in T-cell lym- phomas, both on tumor cells and in their microenviron- ment. PD-L1 is expressed on tumor cells in less than 10% of ALCL and adult T-cell lymphoma / leukemia (ATLL), 27% of cutaneous T-cell lymphoma (CTCL), approxi- mately 60% of PTCL-NOS, 56-80% of ENKTL and 70- 93% of angio-immunoblastic T-cell lymphoma (AITL).154 In both ALK negative and positive ALCL, and in CTCL, PD-L1 overexpression occurs through the STAT3 path- way.154 Like in B-cell lymphomas, structural variations dis- rupting the 3’ region of the PD-L1 gene (27% of ATLL) and EBV infection (particularly in ENKTL) are also responsible for PDL-1 expression.
FAS-L is expressed in 12% of ALCL,153 81% of mycosis fungoid (MF),155 and a majority of CTCL156 which may lead to the elimination of CTL (through FAS-induced death) and to a worse outcome.155,156
Finally, IDO may also contribute to immune escape in ATLL and is associated with a worse outcome.157
Implications for immunotherapy
Restoring antigen recognition
When tumor cells hide from the immune system by pre- venting Ag presentation, strategies to circumvent this escape mechanism depend on the type of lesions (Table 1).
If antigen presentation deficiency results from genetic irreversible lesions, then immunotherapies that are MHC- independent may bypass the lack of antigen presentation. This can be achieved with bi-specific T-cell engager anti- bodies (BiTE) or CAR T cells which target surface antigens
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