Journal
IMMUNITY
Volume 50, Issue 1, Pages 181-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2018.11.014
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Funding
- National Institutes of Health [R01NS045937, P01AI073748, R01CA187975]
- American Cancer Society [RSG-11-057-01-LIB]
- Klarman Cell Observatory at the Broad Institute
- Klarman Cell Observatory at the HHMI
- EMBO long-term fellowship
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An improved understanding of the anti-tumor CD8(+) T cell response after checkpoint blockade would enable more informed and effective therapeutic strategies. Here we examined the dynamics of the effector response of CD8(+) tumor-infiltrating lymphocytes (TILs) after checkpoint blockade therapy. Bulk and single-cell RNA profiles of CD8(+) TILs after combined Tim-3+PD-1 blockade in preclinical models revealed significant changes in the transcriptional profile of PD-1(-)TILs. These cells could be divided into subsets bearing characterstics of naive-, effector-, and memory-precursor-like cells. Effector- and memory-precursor-like TILs contained tumor-antigen-specific cells, exhibited proliferative and effector capacity, and expanded in response to different checkpoint blockade therapies across different tumor models. The memory-precursor-like subset shared features with CD8(+) T cells associated with response to checkpoint blockade in patients and was compromised in the absence of Tcf7. Expression of Tcf7/Tcf1 was requisite for the efficacy of diverse immunotherapies, highlighting the importance of this transcriptional regulator in the development of effective CD8(+) T cell responses upon immunotherapy.
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