Multi-omics, spatial, and functional atlas of CD8+T cell-states regulating differential efficacy of cancer immunotherapy
Prof. Abhishek D. Garg
Tuesday, September 13, 2022
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Introduction
Presentation: Prof. Abhishek D. Garg
Immunotherapeutic modulation of exhausted CD8+T cell populations underscores immune-checkpoint blockers’ (ICBs)-efficacy
Current clinical interpretation of CD8+T cell exhaustion biomarkers is “imperfect”
Dissecting CD8+T cell exhaustion vs. dysfunction and their immunotherapeutic susceptibilities
Benchmarking with “reference” CD19-CAR CD8+T single-cell profiles
A continuum of CD8+T cell-landscapes across tumour-types, with high (SKCM/LUAD) and low (GBM) ICB-responsive cancers exhibiting contradictory exhaustion (EXT) vs. severe-dysfunction (SDF) features
Defects in CD4+T cell-enrichment distinguish the immuno-suppressive, CD8+TSDF cells-“rich” GBM landscape
Defects in optimal antigen-recognition distinguish the CD8+TSDF “enriching” GBM, thereby suggesting existence of contradictory T cell-states between SKCM and GBM
GBM-infiltrating CD8+T cells exhibit TCR non-stimulated or bystander-like (anergic) status
GBM-infiltrating CD8+T cells exhibit dysfunctional single-cell trajectories lacking effector-memory phenotypes
Disparaties in effector/cytolytic signalling factors are largely shared across CD8+T cells infiltrating various neo-adjuvant ICB non-responsive tumour types
GBM-CD8+TSDF show higher cell death or non-proliferative late-regulatory FOXP3+ state
Maladaptive pro-death stress responses and immunosuppressive gene-regulatory networks distinguish CD8+TEXT from CD8+TSDF cells
TGFβ/wound healing pathways define T cell-cancer cell interactions in CD8+TSDF-enriching GBM
Effector, but not TGFβ/wound healing, cytokines augment lymphocytic TCR::NFAT signalling
CD8+TSDF lack effector-polyfunctionality and secrete more wound healing-like chemokines
Bulk-RNAseq and scRNAseq view of a tumour is only “one side of a coin”!
Dissecting spatially-defined CD8+T cell exhaustion/activation states
GBM, unlike SKCM, exhibits spatial disparaties in gaining tumoural access to CD8+T cells
CD4+::CD8+T cell’s spatial-proximity fails to phenotypically-activate CD8+T cells in GBM, but not SKCM
Dissecting spatially-defined CD8+T cell exhaustion/activation states
Spatial gradient of CD8+T cell exhaustion radiates from tumoural blood vessels in GBM
Organ-specific niches, effector signalling vs. TGFβ/wound healing, and CD8+TEXT vs. CD8+TSDF-relevant landscape predict differential ICB-responses
Anti-PD1 immunotherapy facilitates CD8+TSDF-relevant landscape in GBM
Pro-IFNγ/IL2 cellular immunotherapy like DC vaccines can overcome GBM’s CD8+TSDF-enriching landscape?
DC-vaccines rejuvenate antigen-specific immunity in GBM-patients
Tumour-specific, pre-existing CD8+TEXT/TSDF-states, determine immunotherapy-responses with cellular immunotherapy standing the best chance of “provisionally ameliorating” CD8+TSDF-enriching GBM
ACKNOWLEDGEMENTS
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