Abstract
Immune evasion and altered metabolism, where glucose utilization is diverted to increased lactic acid production, are two fundamental hallmarks of cancer. Although lactic acid has long been considered a waste product of this alteration, it is now well accepted that increased lactic acid production and the resultant acidification of the tumor microenvironment (TME) promotes multiple critical oncogenic processes including angiogenesis, tissue invasion/metastasis, and drug resistance. We and others have hypothesized that excess lactic acid in the TME is responsible for suppressing anticancer immunity. Recent studies support this hypothesis and provide mechanistic evidence explaining how lactic acid and the acidic TME impede immune cell functions. In this review, we consider lactic acid’s role as a critical immunoregulatory molecule involved in suppressing immune effector cell proliferation and inducing immune cell de-differentiation. This results in the inhibition of antitumor immune responses and the activation of potent, negative regulators of innate and adaptive immune cells. We also consider the role of an acidic TME in suppressing anticancer immunity. Finally, we provide insights to help translate this new knowledge into impactful anticancer immune therapies.
Highlights
In the 1920s, Otto Warburg first described a phenomenon where cancer cells displayed an altered metabolism, obtaining energy through glycolysis at disproportionately high rates even under aerobic conditions [1]
In order to compensate for the inefficiency in adenosine triphosphate (ATP) production, cancer cells increase their glucose metabolism by regulating key transporters and enzymes [2]
In mouse Natural killer (NK) cells, lactic acid reduces the expression of IFN-γ at both the mRNA and protein levels, and IFNγ production is completely inhibited at 15 mM lactic acid
Summary
In the 1920s, Otto Warburg first described a phenomenon where cancer cells displayed an altered metabolism, obtaining energy through glycolysis at disproportionately high rates even under aerobic conditions [1]. Energy can be derived through the glutaminolytic pathway, where abundant glutamine is metabolized instead of glucose. From both pathways, high amounts of lactic acid are produced and subsequently discharged into the extracellular space between cancer cells (i.e., the tumor microenvironment (TME)). NE u[4m].erNouusmreercoenuts srteucdeinets shtuavdeiesphroavviedpedroveivdieddenecveidseunpceposrutpinpgortthineg ftuhnecftuionncatilonroalleroolef olaf claticcticacaicdidinin iinnhhiibbiittiinngg aannttiiccaanncceerr iimmmmuunniittyy [[55––88]],, aanndd vvaarriioouuss mmeecchhaanniissmmss eexxppllaaiinniinngg hhooww llaaccttiicc aacciidd aanndd tthhee aacciiddiicc TTMMEE iimmppeeddee iimmmmuunneecceellllffuunnccttiioonnsshhaavveeaallssoobbeeeennuunnccoovveerreedd[6[6,9,9––1111].]. WWee wwiillll tthheenn ddeessccrriibbee tthhee mmaajjoorr eeffffeeccttss ooff llaaccttiicc aacciidd aanndd aann aacciiddiicc TTMMEE oonn iimmmmuunnee cceellll ffuunnccttiioonnss..TThheeliltiteerraatuturreessuurvrveeyyeeddhhereereisismmaianilnylyfrofrmomthtihs ipsapsat sdtedcaedcaed, we,iwthitshpescpieacliaatlteanttteionntiopnaipdatiod tthoe tmheosmt roesctenret cdeinsctodviesrcyovthearyt lathctaitc laaccitdicepaicgideneeptiicgaelnlyetriecgaulllyatreesghuilsattoensehmisotodnifiecamtioodnisfi[c1a0t]io. LLaaccttiicc AAcciidd aanndd IInnnnaattee IImmmmuunnee CCeellllss iinn tthhee TTMMEE AA wwiiddee vvaarriieettyy ooffininnnataeteimimmmunuenceelclesllisn tinhetTheMETMplEaypclaruycicarlurcoialelsrionlehsuminahnucmanacnercsa. TLcaesltllsy.,Llaacsttliyc,alcaicdticparocimdoptreosmthoeteisntfihletriantfiiolntraotfioinmomf uimnomsuunpopsruespspivreescsievlle tcyepllesty, psuecsh, sauschMa2smMa2crmopahcraogpehsa(gMe2s)(M-li2k)e-tluikmeotur-masosro-caisastoecdiamteadcrmopachraogpehsa, gNe2s,nNeu2tnroepuhtriolsp(hNil2s)(-Nlik2e)tluikmeotru-amsosor-caiassteodcianteeudtrnoepuhtrilosp, hmilyse, lmoiyde-dloeirdi-vdeedrisvuepdpsruepssporrescseollrs,cealnlsd, raengdulraetgourlyatTorcyelTls,cwellhsi,cwh hcaicnh ecffaencteifvfeeclytivinehlyibiinththibeitatnhteituamntoitruimmomr uimnemruenspeornessepoannsdecaonndtrcibountteritboucteantocecrainmcemruimnemeuscnaepees.cape
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