Citations 1
TIM-3 + CD8 T cells with a terminally exhausted phenotype retain functional capacity in hematological malignancies
Minnie, Simone A. , Waltner, Olivia G. , Zhang, Ping , Takahashi, Shuichiro , Nemychenkov, Nicole S, Ensbey, Kathleen S., Schmidt, Christine R. , Legg, Samuel R.W., Comstock, Melissa , Boiko, Julie R. , Nelson, Ethan , Bhise, Shruti S. , Wilkens, Alec B. , Koyama, Motoko , Dhodapkar, Madhav V. , Chesi, Marta , Riddell, Stanley R. , Spencer, Andrew , Green, Damian J , Spencer, Andrew , Furlan, Scott N , Hill, Geoffrey R , Koyama, Motoko , Hill, Geoffrey R.
Science Immunology | April 19, 2024 | Volume: 9 | Issue: 94 | Pages: No page available
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.