Abstract
Simple SummaryThe growing interest in immunotherapy for the treatment of multiple myeloma demands a deep knowledge of the complex interactions between malignant and immune cells within the bone marrow. Indeed, understanding the cellular and molecular mechanisms underlying this network should represent the basis for the design of novel patient-oriented biological therapeutic approaches. Here, we describe the role of the main immune components of the myeloma niche along disease evolution and their implication in impairing/improving the response to anti-cancer treatments. Additionally, we provided an overview of the potential weakness of this pro-tumor interplay, evidencing novel therapeutic opportunities, which deserve future clinical investigations.Multiple myeloma (MM) is the second most common hematologic malignancy, characterized by a multi-step evolutionary path, which starts with an early asymptomatic stage, defined as monoclonal gammopathy of undetermined significance (MGUS) evolving to overt disease in 1% of cases per year, often through an intermediate phase known as “smoldering” MM (sMM). Interestingly, while many genomic alterations (translocation, deletions, mutations) are usually found at early stages, they are not sufficient (alone) to determine disease evolution. The latter, indeed, relies on significant “epigenetic” alterations of different normal cell populations within the bone marrow (BM) niche, including the “evasion” from immune-system control. Additionally, MM cells could “educate” the BM immune microenvironment (BM-IM) towards a pro-inflammatory and immunosuppressive phenotype, which ultimately leads to disease evolution, drug resistance, and patients’ worse outcome. Indeed, it is not a case that the most important drugs for the treatment of MM include immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide) and monoclonal antibodies (daratumumab, isatuximab, and elotuzumab). On these bases, in this review, we describe the most recent advances in the comprehension of the role of the different cells composing the BM-IM, and we discuss the potential molecular targets, which could represent new opportunities to improve current treatment strategies for MM patients.
Highlights
In recent years, the increased knowledge in cancer immunotherapy has focused many research efforts on the interaction between cancer cells and the immune microenvironment (IM), supporting the concept that IM plays a crucial role in tumor evolution and progression [1–3]
Dendritic cells (DC) are key antigen-presenting cells (APCs), which work as a bridge between innate and adaptive immunity
Within the bone marrow (BM), through different epigenetic modifications [14], DCs are reprogrammed to (1) directly support MM cells proliferation by producing growth cytokines including IL-6, RANK-L, and APRIL with a mechanism dependent on the activation of proinflammatory pathways (p38 and NFkB among others); (2) favor the osteoclastogenesis process; (3) induce Th17 polarization and, mainly, the secretion of IL-17A, which works both as a direct growth factor for MM and as a proinflammatory/bone lysis inducer cytokine; (4) promote neoangiogenesis; (5) genomic instability; (6) protect MM cells from drug-induced apoptosis through the activation of the CD28/CD86 axis [14,19,22,23,51,52]
Summary
The increased knowledge in cancer immunotherapy has focused many research efforts on the interaction between cancer cells and the immune microenvironment (IM), supporting the concept that IM plays a crucial role in tumor evolution and progression [1–3]. By impairing the final part of the differentiation through a strong epigenetic remodeling, MM cells educate differentiating neutrophils to exhibit a pro-inflammatory and pro-tumoral transcriptomic and cytokine profile able to impair lymphocytes response and bispecific drugs activity We demonstrated that this process could be reverted by using hypomethylating agents, making this class of agents be taken into account for combinatory strategy purpose. Neutrophil to lymphocyte ratio (NLR) at diagnosis can predict the outcome in newly diagnosed and post-ASCT MM patients [16,32,33] Overall, these data support the role of an MDSC-oriented therapeutic strategy, which could include JAK/STAT (ruxolitinib), arginase, or phosphodiesterase-5 inhibitors, as well as hypomethylating agents to relieve the immunosuppression and support the activity of concomitant anti-MM (immuno)therapies (Figure 1). Iwndoueendd, ihtehaalisnbge.eOnfsnuogtgee, sMte1datnhdatMw2itshhionutlhdebBeMcomnsiicdreoreendvtihroentmwoenetx,ttruemmoesr-oafssaoccoiantteindumumon; oTcAyMtess ainnddemedacorfotepnhapgreesse(nTtAaMms)ixceodultdrapnrsoctreicpttiMonMal cperllosfiflreom[36t–h3e8r]a.pyIn-itnedreusctiendgalyp, omptoonsoiscyatneds pfppsnihrhraoomorantmwl-ieaccdonluaatlTeossasArirnmi,bceMwaioollsra-eat’mrernrepzoogcoolnioemoloaggicrinnebyiiznitz[naeee3tsds:4iiou(,cs3Cnlc5aaiDp]nns.s1adgi4tcrti−aemelrCsnm(iDsC,tuwDa1nn61he+c4i-e)c+e,hsCttochrDaeecp1lolie6ame−ts[tm2)eo,2rnoi,2nbnt3tehle]yie.rnAmuegsxdecepddodriineataisstnoisedntioi(ea-CnMrlleDyodM1,f 4saCde+tDv/ruu−e1mrg4CasolaDrsnr-ue1pdpc6rhClooormwDatss)1o,mc6taio;nnenidlng-phenCoutyrpreen[t3ly9,].a Dpluetehtoorathoef slaucrkfaocef mshaarrkeedrsdheatevcetiboenenmuestehdodtos,dtehsecrpibeercTeAntMagse(ionfclTuAdiMngs CwDith14in, CMDM20p6a, tCieDn6ts8’,BaMndhCasDb1e6e3n), rwephoicrhtedarteoubseedhigtohliydevnatriifaybalet (lferaosmt twneoarty0pueps otof 2fu5n%c)-, tiifninoofcrnerpceataalitsomiiennansgctsradonwupdrihitnhaMgga2eehvs(iotsgaulhutpetCspio:DrnMe1sf61sr3iov(+miena,fMnl“adaGmlCtUmeDSran2tta0oot6riM+vyeTMoArp, Maw“tcihlitanwhsfisralieytcpr”aao)ltlriyitonsnavicn[ot4dil0vvic–aea4tdet2id]ni.n”gA),aaarnwecgctoiieovrnsgateetsenpidenrosgdiglsuen-raocinsneidlgsl CwumasmtcuotnaunDuooopdtmdudnn1haen6oyo;beCOrlcdcioTrlDalwnyyoeiAch)ttt1vs,tyeeteMsi6ehassva;[an/oee4lsslisdfim3ehnnieiMnd]nonga.vpwdp.cotHehrrOneasoeaCera-tfmptctdiiglnshtecaiyiaosoauvmstpegftesliteasoeiienelc,,rnsanIa,MisI.raflewTpsrmrp1veuehreoeeadorearlfsnnularaaIerderoKclceniceceazmZtModydarFgataety2ie1nicnpoms-disrIrznoMh(RyeiCepxossFp:GeDefuh4audcnUla/1tldnttga4IStaecRser−btrtCsacsFiineiooonD5c,dnnmcsaaw1oecalixp6prnlmh,ii+(alsps)Ciperip,ctditerDthisaiehdoenin1srenrrgte4eeieaoln/n+dclalCiegtrmteieptstDnshtesporhgar1eoosrer6botfnatyii−wegral)petit,dranhoohavni[geemnd3eatntc6xirenmegoio–txcvrretn3peimeyenn8sdrmp-ti]geehdp.issdecetertIssiaehnrsiapogeshotetreendeefirofnrsaat-aeo,(tptlCsimufcteintuoemDiaCgansmnd1tDogctuia4oirnle1nrrya+rlgee4/--ll−, pproolamrioztaitnigonpohfemnoatcyrpopeh[3ag9]e.sD, aunedtiotstthaergleatcikngofexsehratreeddbdyeItMecitDiosndemmeothnosdtrsa,tethdethpeerrececonvtaegrye ooff TanAManstiw-tuitmhionrMfuMncptiaotnieanl tsst’aBtuMs [h4a4s].bTeehnisreevpeonrttecdoutoldbceohnitgrhiblyutveatroiatbhlee b(frriollmianntecalrin0icuapl troes2u5l%ts),aicnhcireevaesdinbgydtuhreincgomevboinluattiioonnforof mIMMiDGsUwSittho mMyMe,lowmitahtraerpgoertitnsginmdiocnaoticnlgonaawl aonrstiepbroodgiensossuiscfhoarspdaatireantutsmwuimthaab haingdhiCsaDtu1x6i3m+ aabn,dwChDos2e06a+ctTivAiMty rinelfiieltsriantiponar[t4o0n–4th2]e. pArerseecnecnet soifnfgulen-ccteiollnsatlumdyacrreovpehaalegdesth[1a1t,4e5v,e4n6].ifFruerdtuhceerddriungMs,GsuUcSh caosmanptair-eCdDt4o7 manotsibt oaddiveasn[c4e7d], iron chelators [48], cyclophosphamides [46], and trabectedin [49], are currently under investigation for their activity on MM-TAMs (Figure 1)
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