Journal
IMMUNITY
Volume 54, Issue 12, Pages 2825-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2021.11.004
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Funding
- German Research Foundation (DFG) project EV-RNA [SE 2331/2-1]
- Eurostars project - German Ministry of Education and Research (BMBF) [E!10865-LeukeMab, 01QE1716]
- German JoseCarreras Foundation [13R/2018]
- German Cancer Aid [70114114, 112069]
- NCT 3.0 funding program [NCT3.0_2015.13 ImmunOmics, NCT3.0_2015.2 SPL/RP]
- Ministerio de Ciencia e Innovacien
- ERDF [SAF15-67633-R]
- la CaixaFoundation [CLLEvolution-LCF/PR/HR17/521500 17, HR17-00221]
- European Research Council (ERC) [810287]
- DFG [SFB1074]
- ERC (ERC-CoG) [648145]
- BMBF-Network PRECiSe [031L0076A]
- ERA-NET TRANSCAN-2 program JTC 2014-project FIRE-CLL
- European Research Council (ERC) [648145] Funding Source: European Research Council (ERC)
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The balance between PD-1(hi) exhausted CD8(+) T cells and functional PD-1(i)(nt) TCF-1(+) CD8(+) T cells is regulated by cell-intrinsic IL-10R signaling, which impacts the immune response and tumor progression. Low levels of IL-10 expression or loss of IL-10R-STAT3 signaling are associated with increased frequencies of exhausted CD8(+) T cells and poor survival in CLL and breast cancer patients.
T cell exhaustion limits anti-tumor immunity and responses to immunotherapy, Here, we explored the microenvironmental signals regulating T cell exhaustion using a model of chronic lymphocytic leukemia (CLL). Single-cell analyses identified a subset of PD-1(hi), functionally impaired CD8(+) T cells that accumulated in secondary lymphoid organs during disease progression and a functionally competent PD-1(int) subset. Frequencies of PD-1(i)(nt) TCF-1(+) CD8(+) T cells decreased upon Il10rb or Stat3 deletion, leading to accumulation of PD-1(hi) cells and accelerated tumor progression. Mechanistically, inhibition of IL-10R signaling altered chromatin accessibility and disrupted cooperativity between the transcription factors NFAT and AP-1, promoting a distinct NFAT-associated program. Low IL10 expression or loss of IL-10R-STAT3 signaling correlated with increased frequencies of exhausted CD8(+) T cells and poor survival in CLL and in breast cancer patients, Thus, balance between PD-1(hi), exhausted CD8(+) T cells and functional PD-1(i)(nt) TCF-1(+) CD8(+) T cells is regulated by cell-intrinsic IL-10R signaling, with implications for immunotherapy.
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