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TIM-3 + CD8 T cells with a terminally exhausted phenotype retain functional capacity in hematological malignancies

GSE262306 Mus musculus Expression profiling by high throughput sequencing; Other 8 samples Submitted 2024/04/19 Platform GPL30172
Summary
Chronic antigen stimulation is thought to generate dysfunctional CD8 T cells. Here we identify a CD8 T cell subset in the bone marrow tumor microenvironment that, despite an apparent terminally exhausted phenotype (TPHEX), expressed granzymes, perforin, and IFNγ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with BATF expression and motif accessibility. IFNγ+ TPHEX effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFNγ+ TPHEX. We also observed IFNγ+ TPHEX within CD19-targeted chimeric antigen receptor T cells, which killed CD19+ leukemia cells. Importantly, an IFNγ+ TPHEX gene signature was recapitulated in TEX cells from human cancers, including myeloma and lymphoma. Here we characterize a TEX subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional TEX found in chronic viral infections. Thus, IFNγ+ TPHEX represent a potential target for immunotherapy of blood cancers.
Published in
TIM-3(+) CD8 T cells with a terminally exhausted phenotype retain functional capacity in hematological malignancies
Minnie SA, Waltner OG, Zhang P et al. · Science immunology 2024 · PMID 38640253 · doi:10.1126/sciimmunol.adg1094
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Also filed as BioProject PRJNA1091196 and SRA study SRP497415. Searching any of these in the dataset finder brings you back here.

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