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 (T), expressed granzymes, perforin, and IFN-γ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with expression and motif accessibility. IFN-γ T effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFN-γ T. We also observed IFN-γ T within CD19-targeted chimeric antigen receptor T cells, which killed CD19 leukemia cells. An IFN-γ T gene signature was recapitulated in T cells from human cancers, including myeloma and lymphoma. Here, we characterize a T subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional T found in chronic viral infections. Thus, IFN-γ T represent a potential target for immunotherapy of blood cancers.