Defining cellular and molecular mechanisms underlying cancer immunotherapy-induced autoinflammatory syndromes.

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Checkpointinhibitors(CPIs)aretransformingtreatmentofseveralsolidtumours(1).Therationalefortheirmechanismcentreson breakingimmunetolerancetotumourantigenstoenableeffectorTcellstokilltumourcells.Thisisachievedbyinhibitingimmune checkpointmolecules(suchasCTLA-4andPD-1)onT cellstoovercomeimmunesuppression(2).Alimitation ofthesetherapiesis the emergence of a range of autoinflammatory syndromes, collectively termed immune-related adverse events (IRAEs), that phenocopy a range of autoimmune diseases (3). IRAEs can affect any organ or tissue but most frequently target skin, gastrointestinal,endocrineandmusculoskeletalsystems.Theycanbesevereorevenfatal(4-5)andincidenceishigh(e.g.incidence of any grade IRAEs targeting multiple organs in a cohort of patients (N=175) receiving CPI therapy in the Cancer Centre at Guy's and St Thomas' NHS Foundation Trust (GSTFT) is65%).IRAEs phenocopy several autoimmune diseases suggesting IRAEs and these diseases may share pathogenic mechanisms resulting inlossoftolerance(6).StudyofIRAEsmaythusyieldopportunisticdiscoveriesintheaetiologiesofautoimmunediseases.Further, some studies have associated IRAE incidence with improved survival outcomes for cancer patients receiving CPI therapy (7-8), suggesting mechanistic links between IRAEs and anti-cancer immunity. However, the cellular and molecular drivers of IRAEs are currently undetermined. Guidance for treatment of IRAEs is suspension of CPI therapy until resolution (4) hence IRAE treatment has the potential to hinder CPI efficacy, in addition to presenting a risk to patientsthemselves.The Pathobiology of Adverse Immune Reactions (PAIR) Study is an active prospective cohort study collecting longitudinal blood samples from GSTFT patients receiving CPIs for treatment of several cancer types for mechanistic studies of IRAEs. The proposed project seeks to probe PAIR Study samples to elucidate the earliest phenotypic changes in peripheral immune cell populations induced by CPIs, and to determine whether detection of these changes at their earliest detectable stage could allow for identification of biomarkers of IRAE risk. We thus aim to address both critical scientific and clinical needs surrounding IRAEs. Preliminary data from our lab suggest serum levels of several soluble inflammatory mediators may indicate likelihood of IRAE development, and that mass cytometry can be used to track immune cell phenotypic changes across serial bloodsamples of PAIR Study subjects to study CPI-induced changes. These data support our proposed experimental approach and hypotheses (see below).My experimental goals are to:1.DeeplyphenotypeperipheralimmunecellpopulationspresentinPAIRpatientPBMCsamplesusingmasscytometryalongside unsupervised data analysis techniques to identify (a) the earliest CPI-induced phenotypic changes and (b) differences in the baseline immune cell phenotypes of patients experiencing different grades ofIRAEs.2.Validate identified cell populations using flowcytometry.3.Functionally characterise effector populations that may be drivingIRAEs.4.Test whether CPI treatment of baseline PBMC samples in vitro can induce cellular and molecular responses observed in vivo, and whether these responses are augmented in samples from patients who proceed to developIRAEs.