%0 Journal Article
%T TIM-3+ CD8 T cells with a terminally exhausted phenotype retain functional capacity in hematological malignancies.
%A Minnie SA
%A Waltner OG
%A Zhang P
%A Takahashi S
%A Nemychenkov NS
%A Ensbey KS
%A Schmidt CR
%A Legg SRW
%A Comstock M
%A Boiko JR
%A Nelson E
%A Bhise SS
%A Wilkens AB
%A Koyama M
%A Dhodapkar MV
%A Chesi M
%A Riddell SR
%A Green DJ
%A Spencer A
%A Furlan SN
%A Hill GR
%J Sci Immunol
%V 9
%N 94
%D 2024 Apr 19
%M 38640253
%F 30.63
%R 10.1126/sciimmunol.adg1094
%X 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 IFN-γ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with BATF expression and motif accessibility. IFN-γ+ TPHEX effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFN-γ+ TPHEX. We also observed IFN-γ+ TPHEX within CD19-targeted chimeric antigen receptor T cells, which killed CD19+ leukemia cells. An IFN-γ+ 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, IFN-γ+ TPHEX represent a potential target for immunotherapy of blood cancers.