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A T cell resilience model associated with response to immunotherapy in multiple tumor types

Authors :
Zhang, Yu
Vu, Trang
Palmer, Douglas C.
Kishton, Rigel J.
Gong, Lanqi
Huang, Jiao
Nguyen, Thanh
Chen, Zuojia
Smith, Cari
Livák, Ferenc
Paul, Rohit
Day, Chi-Ping
Wu, Chuan
Merlino, Glenn
Aldape, Kenneth
Guan, Xin-yuan
Jiang, Peng
Source :
Nature Medicine; July 2022, Vol. 28 Issue: 7 p1421-1431, 11p
Publication Year :
2022

Abstract

Despite breakthroughs in cancer immunotherapy, most tumor-reactive T cells cannot persist in solid tumors due to an immunosuppressive environment. We developed Tres (tumor-resilient T cell, https://resilience.ccr.cancer.gov/), a computational model utilizing single-cell transcriptomic data to identify signatures of T cells that are resilient to immunosuppressive signals, such as transforming growth factor-β1, tumor necrosis factor-related apoptosis-inducing ligand and prostaglandin E2. Tres reliably predicts clinical responses to immunotherapy in melanoma, lung cancer, triple-negative breast cancer and B cell malignancies using bulk T cell transcriptomic data from pre-treatment tumors from patients who received immune-checkpoint inhibitors (n= 38), infusion products for chimeric antigen receptor T cell therapies (n= 34) and pre-manufacture samples for chimeric antigen receptor T cell or tumor-infiltrating lymphocyte therapies (n= 84). Further, Tres identified FIBP, whose functions are largely unknown, as the top negative marker of tumor-resilient T cells across many solid tumor types. FIBPknockouts in murine and human donor CD8+T cells significantly enhanced T cell-mediated cancer killing in in vitro co-cultures. Further, Fibpknockout in murine T cells potentiated the in vivo efficacy of adoptive cell transfer in the B16 tumor model. Fibpknockout T cells exhibit reduced cholesterol metabolism, which inhibits effector T cell function. These results demonstrate the utility of Tres in identifying biomarkers of T cell effectiveness and potential therapeutic targets for immunotherapies in solid tumors.

Details

Language :
English
ISSN :
10788956 and 1546170X
Volume :
28
Issue :
7
Database :
Supplemental Index
Journal :
Nature Medicine
Publication Type :
Periodical
Accession number :
ejs59586395
Full Text :
https://doi.org/10.1038/s41591-022-01799-y