{Reference Type}: Journal Article
{Title}: TIM-3+ CD8 T cells with a terminally exhausted phenotype retain functional capacity in hematological malignancies.
{Author}: Minnie SA;Waltner OG;Zhang P;Takahashi S;Nemychenkov NS;Ensbey KS;Schmidt CR;Legg SRW;Comstock M;Boiko JR;Nelson E;Bhise SS;Wilkens AB;Koyama M;Dhodapkar MV;Chesi M;Riddell SR;Green DJ;Spencer A;Furlan SN;Hill GR;
{Journal}: Sci Immunol
{Volume}: 9
{Issue}: 94
{Year}: 2024 Apr 19
{Factor}: 30.63
{DOI}: 10.1126/sciimmunol.adg1094
{Abstract}: 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.