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

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. Mouse polyclonal CD8 T cells were harvested from BM and were sequenced for gene expression (3'; 1 sample) and for concurrent ATAC and RNA seq (Multi-ome; 3 samples). Mouse CD19 CAR T cells were harvested from BM and sequenced for gene expression and TCR repertoire (5'; 1 sample) Please note that the processed data for the 'scMO_MM_CD8* samples are linked as Series supplementary files.