| Autor: |
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., Green, Damian J., Spencer, Andrew, Furlan, Scott N. |
| Předmět: |
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| Zdroj: |
Science Immunology; 2024, Vol. 9 Issue 94, p1-18, 18p |
| Abstrakt: |
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. Editor's Summary: Chronic antigen stimulation can drive CD8 T cell exhaustion and dysfunction among multiple T cell subsets. Using a murine myeloma model, Minnie et al. characterized a terminally exhausted CD8 T cell subset in the bone marrow tumor microenvironment that expressed not only transcription and epigenetic factors associated with exhaustion but also effector molecules, including IFN-γ, granzymes, and perforin. This subset, IFN-γ+ TPHEX (IFN-γ–secreting, phenotypically exhausted T cells), could kill myeloma cells, and IFN-γ+ TPHEX differentiated from CD19-targeted chimeric antigen receptor T cells could kill CD19+ tumor cells. An analogous IFN-γ+ TPHEX subset was also detected in patients with myeloma and lymphoma. Together, these findings suggest that IFN-γ+ TPHEX have dysfunctional features but retain functionality, facilitating antitumor responses. —Christiana Fogg [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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