Cancer development accompanies with the dynamic evolution of immunity, a well-known process termed as immunoediting. However, the underlying mechanisms of the transition between each phase, from immune surveillancetofinalescape,stillremainalottodiscover.Thisproposalaimstostudyimmunoeditingduringliver cancerdevelopmentandprogression, with a focus on senescenceand metastasis. Senescence isa cell cycle arrestprogramthatlimitstheexpansionofdamagedcellsandcantriggeranti-tumorimmunitythatleadstotheir elimination in vivo, serving as a potent barrier to tumorigenesis. However, during tumor initiation, the effective clearanceof senescent cells is compromised, warranting a deeper mechanisticunderstanding of this process. Mydoctoralresearchaimstoidentifycriticalmolecularandcellularplayersdrivinganti-tumorimmuneresponses during senescence surveillance triggeredby wildtypep53, which is knownto modulates cancer immunity. The long-termobjective of my thesis project is todefine the mechanismsof how senescent cells are susceptible to immune surveillance and how these mechanisms are evaded or bypassed during cancer development and progression.AsdescribedinSpecificAims1.1-1.3,mythesisworkhasdemonstratedthatthep53restoration triggersregressionoflivercancersinanimmunocompetenthost.Usingdifferentimmunodeficientmousestrains andpharmacologicalapproachesperturbingspecificimmunecompartments,ourpreliminarydatasuggeststhat adaptive immunity plays a key role in senescence surveillance. RNA-seq and mass spectrometry were conducted on both proliferating and senescent tumor cells and revealed several senescence-enriched cell surfacefactorsrelatedtoepithelial-immunecellinteractions.
In SpecificAims1. 4and1.5,weaimtofunctionally interrogate the role of these senescence-induced factors as novel senescence surveillance effectors, with a focus on the regulatory network of antigenpresentationpathway and, byexploiting multiplexed in vivo genetic screensestablishedintheLowelaboratory.Mypostdoctoralresearchwillcontinuetostudyimmunoeditingwith a slight changeofthe focus from the epithelial-tumor angle to a more immunology-richperspective,appliedto theproblemofmetastaticimmuneescape.TheproposalaimstoinvestigatethemolecularchangesofNKcells, showntohavecontrolofearlymetastasis,afterhavingphysicalinteractionwithmetastaticcells.Duringdifferent stages of metastatic colonization, tumor-engaging NK cells are labeled via ?SynNotch? technology and will be subjectedtosingle-cellRNA-seqtounveiltheNKcellheterogeneity(SpecificAim2.1)andATAC-seqtoreveal potential epigenetic mechanisms of immune exhaustion with functional perturbation of the altered programs employed(SpecificAim2.2).Theproposedpostdoctoralresearchwillincreaseourmechanisticunderstanding ofNKbiologyduringthemetastasisoutbreak,pavingnewpathstoharnessinnateimmunityagainstcancer.In all,thesetwoprojectswillofferdistinctinsightintoimmunoediting,ofwhichtheelucidatedmechanismscouldbe exploitedfordevelopingnovelimmunotherapies,jointlywithexistingonesformoreeffectivecancercontrol.
Despite recent advances in immunotherapy that lead to substantial increase of cancer patient survival, still a greatportionofpatientsarenotresponsivetothetreatment,underscoringtheneedforadeeperunderstanding ofhowtumorcellsandimmunesysteminteractwitheachother.Inthisproject,theproposeddoctoralresearch aimstoelucidatethemolecularmechanismsviawhichcellularsenescencetriggersimmunesurveillanceagainst liver cancer in vivo, with theultimategoal of identifyingnew strategies to pharmacologically mimicor enhance theseeffects.TheproposedpostdoctoralresearchwillinvestigateNKcell-basedmechanismsofimmuneescape during extrahepatic metastasis of liver tumors to lung, which could offer novel insights into re-activating this innateimmunitytotargetthisend-stagecancer.
