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M. de Charette et al.
without the need for MHC.158,159
If antigen presentation deficiency results from epigenet-
ic reversible lesions, then one may use therapies which can induce re-expression of MHC, co-stimulatory or adhe- sion molecules, such as epigenetic drugs, chemotherapy, radiotherapy or certain immunotherapies (e.g. CD40 ago- nists, CpG, IFN).7,160 Notably, the addition of histone deacetylase inhibitor (HDACI) to R-CHOP restored MHC-II expression161 and erased the negative prognostic value associated with MHC-II loss in DLBLC.162
Restoring cell death
BCL-2 inhibitors, such as venetoclax, may sensitize tumor cells to death induced through the intrinsic path- way. They have a strong efficacy in CLL and, to a lesser extent, in some NHL (MCL, FL, DLBCL).163 Surprisingly, despite the pathophysiological importance of BCL-2 translocation in FL, venetoclax demonstrated only poor efficacy in this disease.
In pre-clinical models, Gal-3 inhibitor can disturb CD45/Gal-3 interaction and restore apoptosis.137
Blocking inhibitory signals
Immune checkpoint (ICP) blockade releases inhibition of effector cells but requires an intact antigen presentation and a pre-existing anti-tumor immune response. Blockade of CTLA4, PD1 and PD-L1 have demonstrated efficacy in solid tumors and hematologic malignancies.158 Surprisingly, anti-PD1 mAbs were found to be particularly efficient in HL despite the fact that MHC expression was lost in most cases, suggesting an alternative mechanism of action.
Phagocytosis may be blocked by CD47 signaling. Blocking antibodies against CD47 or SIRPa can disrupt CD47-SIRPa interaction and restore phagocytosis. Blocking CD47 signaling may also potentiate the efficacy of anti-CD20 mAb by increasing antibody-dependent cel- lular phagocytosis (ADCP).112-114
Modulating the tumor microenvironment
Immunosuppressive macrophages may be depleted by
depletion may be achieved with anti-CTLA4 mAbs (such as ipilimumab)166,167 or mAbs against CCR-4 (such as moga- mulizumab) which is preferentially expressed by Th2 and Tregs.141,168 Treg infiltration may also be decreased by low doses of cyclophosphamide through downregulation of FOXP3.160 IDO enzyme may be down-regulated using IDO inhibitors or fludarabine.169,170
Conclusion
The recent success of ICP blocking antibodies in cancer patients confirmed the hypothesis of “cancer immuno- surveillance” and demonstrated the potency of immunotherapy for the treatment of cancer. The goal of immunotherapy is to re-educate the immune system and to reverse the immune escape mechanisms to destroy the tumor cells.
B-cell lymphoma is unique because tumor cells are pro- fessional APC and therefore can present their own anti- gens to the immune system. Immune escape in lymphoma may occur at the priming or at the effector phase. It may result from defects in antigen presentation (which may prevent the priming of T cells or the recognition of tumor cells at the effector phase), from resistance to immune killing, or from immunosuppressive mechanisms (either directly by the tumor cells or indirectly by their microen- vironment).
The advent of new classes of immunotherapies (includ- ing checkpoint inhibitors, bispecific antibodies and CAR T cells) offers novel opportunities to mobilize the immune system against lymphoma.159 However, we need to deter- mine which of these immunotherapies will be optimal for a given patient. Furthermore, some immune escape mech- anisms may dampen the efficacy of these immunothera- pies and may require combination with other therapies to sensitize tumor cells to immune eradication. The charac- terization of immune escape mechanisms may be used to guide “personalized immunotherapy”, i.e. determine the optimal immunotherapy and/or combination in a given lymphoma patient.
chemotherapy164 or anti-CSF-1 receptor
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