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Bile acids modified by the intestinal microbiota promote colorectal cancer growth by suppressing CD8+ T cell effector functions.

Jingjing Cong | Pianpian Liu | Zili Han | Wei Ying | Chaoliang Li | Yifei Yang | Shuling Wang | Jianbo Yang | Fei Cao | Juntao Shen | Yu Zeng | Yu Bai | Congzhao Zhou | Lilin Ye | Rongbin Zhou | Chunjun Guo | Chunlei Cang | Dennis L Kasper | Xinyang Song | Lei Dai | Linfeng Sun | Wen Pan | Shu Zhu
Immunity | 2024

Concentrations of the secondary bile acid, deoxycholic acid (DCA), are aberrantly elevated in colorectal cancer (CRC) patients, but the consequences remain poorly understood. Here, we screened a library of gut microbiota-derived metabolites and identified DCA as a negative regulator for CD8+ T cell effector function. Mechanistically, DCA suppressed CD8+ T cell responses by targeting plasma membrane Ca2+ ATPase (PMCA) to inhibit Ca2+-nuclear factor of activated T cells (NFAT)2 signaling. In CRC patients, CD8+ T cell effector function negatively correlated with both DCA concentration and expression of a bacterial DCA biosynthetic gene. Bacteria harboring DCA biosynthetic genes suppressed CD8+ T cells effector function and promoted tumor growth in mice. This effect was abolished by disrupting bile acid metabolism via bile acid chelation, genetic ablation of bacterial DCA biosynthetic pathway, or specific bacteriophage. Our study demonstrated causation between microbial DCA metabolism and anti-tumor CD8+ T cell response in CRC, suggesting potential directions for anti-tumor therapy.

Pubmed ID: 38479384 RIS Download

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Anti-TNF-alpha Rabbit pAb (antibody)

RRID:AB_3075517

This polyclonal targets TNF-alpha

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Interferon gamma antibody (antibody)

RRID:AB_448613

This polyclonal targets Interferon gamma antibody

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Granzyme B Antibody (antibody)

RRID:AB_3075510

This monoclonal targets Granzyme B

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InVivoPlus anti-mouse CD8α (antibody)

RRID:AB_1107671

This monoclonal targets CD8α

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HRP-labeled Goat Anti-Rabbit IgG (H+L) (antibody)

RRID:AB_2892644

This polyclonal secondary targets IgG (H+L)

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PMCA1 Antibody (5F10) (antibody)

RRID:AB_2091527

This monoclonal targets PMCA1

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PMCA4 Antibody (antibody)

RRID:AB_2061726

This monoclonal targets PMCA4

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GAPDH antibody (antibody)

RRID:AB_2107436

This monoclonal targets GAPDH

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Lamin B1 antibody (antibody)

RRID:AB_11232208

This monoclonal targets Lamin B1

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Phospho-PLCgamma1 (Tyr783) Antibody (antibody)

RRID:AB_330855

This polyclonal targets Phospho-PLCgamma1 (Tyr783)

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Phospho-LAT (Tyr191) Antibody (antibody)

RRID:AB_2157728

This unknown targets LAT, phospho (Tyr191)

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Phospho-Src Family (Tyr416) Antibody (antibody)

RRID:AB_331697

This polyclonal targets Phospho-Src Family (Tyr416)

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Phospho-Zap-70 (Tyr319)/Syk (Tyr352) (65E4) Rabbit mAb (antibody)

RRID:AB_2218658

This monoclonal targets Phospho-Zap-70 (Tyr319)/Syk (Tyr352)

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Beta Actin antibody (antibody)

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Granzyme B (antibody)

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FITC anti-human IFN-gamma (antibody)

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PE anti-human TNF-alpha (antibody)

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CD3e (antibody)

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APC anti-mouse CD25 (antibody)

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This monoclonal targets CD25

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APC anti-mouse TNF-alpha (antibody)

RRID:AB_315428

This monoclonal targets TNF-alpha

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APC anti-mouse CD279 (PD-1) (antibody)

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This monoclonal targets CD279

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PE/Cyanine7 anti-mouse CD3 (antibody)

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This monoclonal targets CD3

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PE/Cyanine7 anti-mouse TCR beta chain (antibody)

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PE/Cyanine7 anti-mouse IFN-gamma (antibody)

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This monoclonal targets IFN-gamma

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PerCP anti-mouse CD45 (antibody)

RRID:AB_893339

This monoclonal targets CD45

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PE anti-mouse CD279 (PD-1) (antibody)

RRID:AB_313421

This monoclonal targets CD279

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PE anti-human/mouse Granzyme B Recombinant (antibody)

RRID:AB_2687031

This recombinant monoclonal targets Granzyme B

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PE anti-mouse Ki-67 (antibody)

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FITC anti-mouse CD4 (antibody)

RRID:AB_312691

This monoclonal targets CD4

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FITC anti-mouse/human CD44 (antibody)

RRID:AB_493684

This monoclonal targets CD44

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FITC anti-mouse CD45.2 (antibody)

RRID:AB_313442

This monoclonal targets CD45.2

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C57BL/6JGpt-Rag1em1Cd3259/Gpt (organism)

RRID:IMSR_GPT:T004753

Mus musculus with name C57BL/6JGpt-Rag1em1Cd3259/Gpt from IMSR.

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C57BL/6JGpt (organism)

RRID:IMSR_GPT:N000013

Mus musculus with name C57BL/6JGpt from IMSR.

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STOCK Nr1h4tm1Gonz/J (organism)

RRID:IMSR_JAX:004144

Mus musculus with name STOCK Nr1h4tm1Gonz/J from IMSR.

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HEK293T (cell line)

RRID:CVCL_0063

Cell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)

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B6.129S4-Vdrtm1Mbd/J (organism)

RRID:IMSR_JAX:006133

Mus musculus with name B6.129S4-Vdrtm1Mbd/J from IMSR.

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C57BL/6N-Gpbar1tm1(KOMP)Vlcg/MbpMmucd (organism)

RRID:MMRRC_047915-UCD

Mus musculus with name C57BL/6N-Gpbar1tm1(KOMP)Vlcg/MbpMmucd from MMRRC.

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B6.129S4-Vdrtm1Mbd/J (organism)

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Mus musculus with name B6.129S4-Vdrtm1Mbd/J from IMSR.

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C57BL/6N-Gpbar1tm1(KOMP)Vlcg/MbpMmucd (organism)

RRID:MMRRC_047915-UCD

Mus musculus with name C57BL/6N-Gpbar1tm1(KOMP)Vlcg/MbpMmucd from MMRRC.

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Anti-TNF-alpha Rabbit pAb (antibody)

RRID:AB_3075517

This polyclonal targets TNF-alpha

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Interferon gamma antibody (antibody)

RRID:AB_448613

This polyclonal targets Interferon gamma antibody

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InVivoPlus anti-mouse CD8α (antibody)

RRID:AB_1107671

This monoclonal targets CD8α

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Granzyme B Antibody (antibody)

RRID:AB_3075510

This monoclonal targets Granzyme B

View all literature mentions

HRP-labeled Goat Anti-Rabbit IgG (H+L) (antibody)

RRID:AB_2892644

This polyclonal secondary targets IgG (H+L)

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PMCA1 Antibody (5F10) (antibody)

RRID:AB_2091527

This monoclonal targets PMCA1

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PMCA4 Antibody (antibody)

RRID:AB_2061726

This monoclonal targets PMCA4

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GAPDH antibody (antibody)

RRID:AB_2107436

This monoclonal targets GAPDH

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Lamin B1 antibody (antibody)

RRID:AB_11232208

This monoclonal targets Lamin B1

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Phospho-PLCgamma1 (Tyr783) Antibody (antibody)

RRID:AB_330855

This polyclonal targets Phospho-PLCgamma1 (Tyr783)

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Phospho-LAT (Tyr191) Antibody (antibody)

RRID:AB_2157728

This unknown targets LAT, phospho (Tyr191)

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Phospho-Src Family (Tyr416) Antibody (antibody)

RRID:AB_331697

This polyclonal targets Phospho-Src Family (Tyr416)

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Phospho-Zap-70 (Tyr319)/Syk (Tyr352) (65E4) Rabbit mAb (antibody)

RRID:AB_2218658

This monoclonal targets Phospho-Zap-70 (Tyr319)/Syk (Tyr352)

View all literature mentions

Beta Actin antibody (antibody)

RRID:AB_2687938

This monoclonal targets Beta Actin

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Granzyme B (antibody)

RRID:AB_2738175

This monoclonal targets Granzyme B

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FITC anti-human IFN-gamma (antibody)

RRID:AB_315437

This monoclonal targets IFN-gamma

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PE anti-human TNF-alpha (antibody)

RRID:AB_315260

This monoclonal targets TNF-alpha

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CD3e (antibody)

RRID:AB_11153670

This monoclonal targets CD3e

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APC anti-mouse CD25 (antibody)

RRID:AB_312860

This monoclonal targets CD25

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APC anti-mouse TNF-alpha (antibody)

RRID:AB_315428

This monoclonal targets TNF-alpha

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APC anti-mouse CD279 (PD-1) (antibody)

RRID:AB_2159183

This monoclonal targets CD279

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PE/Cyanine7 anti-mouse CD3 (antibody)

RRID:AB_1732057

This monoclonal targets CD3

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PE/Cyanine7 anti-mouse TCR beta chain (antibody)

RRID:AB_893625

This monoclonal targets TCR beta chain

View all literature mentions

PE/Cyanine7 anti-mouse IFN-gamma (antibody)

RRID:AB_2295770

This monoclonal targets IFN-gamma

View all literature mentions

PerCP anti-mouse CD45 (antibody)

RRID:AB_893339

This monoclonal targets CD45

View all literature mentions

PE anti-mouse CD279 (PD-1) (antibody)

RRID:AB_313421

This monoclonal targets CD279

View all literature mentions

PE anti-human/mouse Granzyme B Recombinant (antibody)

RRID:AB_2687031

This recombinant monoclonal targets Granzyme B

View all literature mentions

PE anti-mouse Ki-67 (antibody)

RRID:AB_2561525

This monoclonal targets Ki-67

View all literature mentions

FITC anti-mouse CD4 (antibody)

RRID:AB_312691

This monoclonal targets CD4

View all literature mentions

FITC anti-mouse/human CD44 (antibody)

RRID:AB_493684

This monoclonal targets CD44

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FITC anti-mouse CD45.2 (antibody)

RRID:AB_313442

This monoclonal targets CD45.2

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