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