MDSCsareoneofthemajortypesofimmunecellsthatcontributetotumor-inducedimmunesuppressionand escape from immune elimination. Importantly, MDSCs have been suggested to contribute to resistance to variouscancertherapies,includingtoanti-CTLA-4andanti-PD-1blockade.Hence,targetingMDSCscouldbe anattractiveapproachtomodulatetumorimmunitytoimprovecurrentcancerimmunotherapies.Wehavevery recently reported that phenformin, a mitochondrial respiratory chain complex I inhibitor, selectively reduced proportionofpolymorphonuclearMDSCs(PMN-MDSCs),butnototherimmunecellsinspleensoftumor-bearing mice.PhenforminalsoinhibitedproliferationofPMN-MDSCsderivedfrombonemarrowco-culturedwithtumor cells in vitro. Furthermore, PMN-MDSCs derived from mice treated with phenformin showed attenuated suppressive activities towards CD8+ T cells in T cell proliferation assays. In our unpublished metabolomics profiling studies of PMN-MDSCs, we have uncovered additional potential metabolic vulnerabilities of PMN- MDSCs.Basedonthesefindings,wehypothesizethatPMN-MDSCspossessdistinguishingmetabolicfeatures. GiventheimportantcontributionofMDSCstotumorimmuneescapeandimmunotherapyresistance,wefurther hypothesizethattargetingthemetabolicvulnerabilitiesofPMN-MDSCsmaycooperatewithimmunecheckpoint blockadetounleashTcellresponses,leadingtoimprovedanti-tumorefficacy.
In aim1, weplantocharacterize themetabolicvulnerabilitiesofPMN-MDSCs.WewillnotonlyelucidatemetabolicfeaturesofPMN-MDSCsthat underlietheirsensitivitytophenformin,butalsoidentifyothermetabolictargetsofPMN-MDSCs,suchasthose involvedintheglutaminemetabolism.
In aim2, wewillassessthetherapeuticbenefitofcombiningtargetingthe metabolic vulnerabilities of PMN-MDSCs with immune checkpoint blockade in mouse cancer models. We will evaluatetheeffectsofmetabolicdrugsincombinationwithanti-PD-1blockade,onthetumormicroenvironment andanalyzethecontributionofPMN-MDSCmodulatoryactivityofthesemetabolicdrugsusingthePMN-MDSC adoptivetransferapproach.
Biological drugs that target the immune checkpoint proteins CTLA-4, PD-1 or PD-L1 have shown significant clinical benefits in solid tumors with durable responses, but only in a fraction of patients. Targeting the immune- suppressive activities of MDSCs with metabolic drugs may synergize with immune checkpoint blockade to enhance immune therapy efficacy. If this hypothesis is proven true, our preclinical studies could be promptly translated into clinical trials.
