PABPC1L Induces IDO1 to Promote Tryptophan Metabolism and Immune Suppression in Renal Cell Carcinoma.
The tumor microenvironment (TME) in renal cell carcinomas (RCC) is marked by substantial immunosuppression and immune resistance despite having extensive T-cell infiltration. Elucidation of the mechanisms underlying immune evasion could help identify therapeutic strategies to boost the efficacy of immune checkpoint blockade (ICB) in RCC. This study uncovered a mechanism wherein the polyadenylate-binding protein PABPC1L modulates indoleamine 2,3-dioxygenase 1 (IDO1), a prospective target for immunotherapy. PABPC1L was markedly upregulated in RCC, and high PABPC1L expression correlated with unfavorable prognosis and resistance to ICB. PABPC1L bolstered tryptophan metabolism by upregulating IDO1, inducing T-cell dysfunction and Treg infiltration. PABPC1L enhanced the stability of JAK2 mRNA, leading to increased JAK2-STAT1 signaling that induced IDO1 expression. Additionally, PABPC1L-induced activation of the JAK2-STAT1 axis created a positive feedback loop to promote PABPC1L transcription. Conversely, loss of PABPC1L diminished IDO1 expression, mitigated cytotoxic T-cell suppression, and enhanced responsiveness to anti-PD-1 therapy in patient-derived xenograft models. These findings reveal the crucial role of PABPC1L in facilitating immune evasion in RCC and indicate that inhibiting PABPC1L could be a potential immunotherapeutic approach in combination with ICB to improve patient outcomes.
Pubmed ID: 38382068 RIS Download
Research resources used in this publication
-
NOD/ShiLtJGpt-Prkdcem26Cd52Il2rg
- C.Cg/AnNTac-Foxn1nu NE9 (RRID:IMSR_TAC:BALBNU) (organism)
- GraphPad Prism (RRID:SCR_002798) (software resource)
- SPSS (RRID:SCR_002865) (software resource)
- Monocle3 (RRID:SCR_018685) (software resource)
- Harmony (RRID:SCR_022206) (software resource)
- Seurat (RRID:SCR_016341) (software resource)
- BALB/cJGpt (RRID:IMSR_GPT:N000020) (organism)
- DESeq2 (RRID:SCR_015687) (software resource)
- HISAT2 (RRID:SCR_015530) (software resource)
- Beckman Coulter CytoFLEX Flow Cytometer (RRID:SCR_019627) (instrument resource)
- HALO (RRID:SCR_018350) (data processing software)
- HEK293T (RRID:CVCL_0063) (cell line)
- RenCa (RRID:CVCL_2174) (cell line)
- Caki-1 (RRID:CVCL_0234) (cell line)
- 769-P (RRID:CVCL_1050) (cell line)
- HK2 (RRID:CVCL_YE28) (cell line)
- BALB/cJGpt (RRID:IMSR_GPT:N000020) (organism)
Additional research tools detected in this publication
Antibodies used in this publication
- Mouse anti DDDDK-Tag mAb (RRID:AB_2770401)
- APC anti-mouse CD3 (RRID:AB_2561455)
- FITC anti-human HLA-A2 (RRID:AB_1659245)
- FITC anti-mouse/human CD11b (RRID:AB_312789)
- APC anti-mouse F4/80 (RRID:AB_893493)
- APC anti-mouse CD19 (RRID:AB_2629839)
- Alexa Fluor(R) 700 anti-mouse FOXP3 (RRID:AB_2750492)
- APC anti-human CD3 (RRID:AB_1937213)
- FITC anti-mouse CD4 (RRID:AB_312691)
- PE anti-mouse CD45 (RRID:AB_2563597)
- PE anti-human/mouse Granzyme B Recombinant (RRID:AB_2687031)
- FITC anti-human/mouse Granzyme B Recombinant (RRID:AB_2687029)
- PE anti-human IFN-gamma (RRID:AB_315235)
- PerCP/Cyanine5.5 anti-human Perforin (RRID:AB_2169092)
- PE anti-mouse Perforin (RRID:AB_2721639)
- FITC anti-mouse CD8a (RRID:AB_312745)
- PE anti-mouse IFN-gamma (RRID:AB_315401)
- PE anti-mouse CD8a (RRID:AB_2894434)
- GAPDH antibody (RRID:AB_2107436)
- FITC anti-human CD8a (RRID:AB_314110)
- CoraLite594 conjugated Goat Anti-Mouse IgG(H+L) (RRID:AB_2797133)
- CoraLite488 conjugated Affinipure Goat Anti-Rabbit IgG(H+L) (RRID:AB_2797132)
- Cleaved Caspase-3 (Asp175) Antibody (RRID:AB_2341188)
- eIF4G (C45A4) Rabbit mAb (RRID:AB_2096028)
- Stat3 (124H6) Mouse mAb (RRID:AB_331757)
- Stat1 (RRID:AB_2737027)
- Jak2 (D2E12) XP Rabbit mAb (RRID:AB_2128522)
- Rabbit Control IgG (RRID:AB_2771930)
- Jak1 (6G4) Rabbit mAb (RRID:AB_2265054)
- Mouse Control IgG (RRID:AB_2770414)
- anti His-Tag (RRID:AB_2728734)
Associated grants
- Agency: National Natural Science Foundation of China (NSFC),
Id: 81772514 - Agency: National Natural Science Foundation of China (NSFC),
Id: 82073381 - Agency: National Natural Science Foundation of China (NSFC),
Id: 81725016 - Agency: National Natural Science Foundation of China (NSFC),
Id: 81872094 - Agency: National Natural Science Foundation of China (NSFC),
Id: 81772718 - Agency: National Natural Science Foundation of China (NSFC),
Id: 82002684 - Agency: Pearl River S and T Nova Program of Guangzhou Municipality (Pearl River S&T Nova Program of Guangzhou),
Id: 201806010005 - Agency: Natural Science Foundation of Guangdong Province (),
Id: S2019B151502046 - Agency: Natural Science Foundation of Guangdong Province (),
Id: 201704020174 - Agency: Natural Science Foundation of Guangdong Province (),
Id: 2023A1515030038 - Agency: China Postdoctoral Science Foundation (China Postdoctoral Foundation Project),
Id: 236464 - Agency: China Postdoctoral Science Foundation (China Postdoctoral Foundation Project),
Id: 2023M730374 - Agency: China Postdoctoral Science Foundation (China Postdoctoral Foundation Project),
Id: 2021TQ0381 - Agency: China Postdoctoral Science Foundation (China Postdoctoral Foundation Project),
Id: 2021M703700 - Agency: Guangzhou Women and Childrens Medical Center (),
Id: 2023BS017 - Agency: Major Basic Research Project of the Natural Science Foundation of the Jiangsu Higher Education Institutions (Key University of Science Research Project of Jiangsu Province),
Id: 23KJB320018 - Agency: Guangzhou Municipal Science and Technology Project (Guangzhou Science and Technology Plan),
Id: 202201010910 - Agency: Changzhou Institute of Technology (CIT),
Id: 2021TQ0381 - Agency: Changzhou Institute of Technology (CIT),
Id: CQ20220129
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RRID:SCR_003145
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View all literature mentionsBALB/cAnNCrl (tool)
RRID:MGI:2683685
laboratory mouse with name BALB/cAnNCrl from MGI.
View all literature mentionsMouse anti DDDDK-Tag mAb (antibody)
RRID:AB_2770401
This monoclonal targets DDDDK-Tag
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RRID:AB_2561455
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RRID:AB_312789
This monoclonal targets CD11b
View all literature mentionsAPC anti-mouse F4/80 (antibody)
RRID:AB_893493
This monoclonal targets F4/80
View all literature mentionsAPC anti-mouse CD19 (antibody)
RRID:AB_2629839
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RRID:AB_2750492
This monoclonal targets FOXP3
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RRID:AB_2687031
This recombinant monoclonal targets Granzyme B
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This recombinant monoclonal targets Granzyme B
View all literature mentionsPE anti-human IFN-gamma (antibody)
RRID:AB_315235
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RRID:AB_2169092
This monoclonal targets Perforin
View all literature mentionsPE anti-mouse Perforin (antibody)
RRID:AB_2721639
This monoclonal targets Perforin
View all literature mentionsFITC anti-mouse CD8a (antibody)
RRID:AB_312745
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RRID:AB_315401
This monoclonal targets IFN-gamma
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RRID:AB_2894434
This monoclonal targets CD8a
View all literature mentionsGAPDH antibody (antibody)
RRID:AB_2107436
This monoclonal targets GAPDH
View all literature mentionsFITC anti-human CD8a (antibody)
RRID:AB_314110
This monoclonal targets CD8a
View all literature mentionsCoraLite594 conjugated Goat Anti-Mouse IgG(H+L) (antibody)
RRID:AB_2797133
This unknown targets IgG(H+L)
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RRID:AB_2797132
This polyclonal secondary targets IgG(H+L)
View all literature mentionsCleaved Caspase-3 (Asp175) Antibody (antibody)
RRID:AB_2341188
This polyclonal targets Cleaved Caspase-3 (Asp175)
View all literature mentionseIF4G (C45A4) Rabbit mAb (antibody)
RRID:AB_2096028
This monoclonal targets EIF4G3
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RRID:AB_331757
This monoclonal targets Stat3
View all literature mentionsJak2 (D2E12) XP Rabbit mAb (antibody)
RRID:AB_2128522
This monoclonal targets Jak2 (D2E12) XP Rabbit mAb
View all literature mentionsJak1 (6G4) Rabbit mAb (antibody)
RRID:AB_2265054
This monoclonal targets Jak1
View all literature mentionsMouse Control IgG (antibody)
RRID:AB_2770414
This unknown targets Mouse Control IgG
View all literature mentionsanti His-Tag (antibody)
RRID:AB_2728734
This monoclonal targets His-Tag
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NOD/ShiLtJGpt-Prkdcem26Cd52Il2rg/Gpt (organism)
RRID:IMSR_GPT:T001475
Mus musculus with name NOD/ShiLtJGpt-Prkdcem26Cd52Il2rg
C.Cg/AnNTac-Foxn1nu NE9 (organism)
RRID:IMSR_TAC:BALBNU
Mus musculus with name C.Cg/AnNTac-Foxn1nu NE9 from IMSR.
View all literature mentionsGraphPad Prism (software resource)
RRID:SCR_002798
Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsSPSS (software resource)
RRID:SCR_002865
Software package used for interactive, or batched, statistical analysis in social science, health sciences and marketing. Software platform offers advanced statistical analysis, a library of machine-learning algorithms, text analysis, open-source extensibility, integration with big data and deployment into applications.Versions that were produced by SPSS Inc. before the IBM acquisition (Versions 18 and earlier) would be given origin or publisher of SPSS Inc. in Chicago.
View all literature mentionsMonocle3 (software resource)
RRID:SCR_018685
Software analysis toolkit for single cell RNA-seq. Used for single cell RNA-Seq experiments. Unsupervised algorithm that increases temporal resolution of transcriptome dynamics using single-cell RNA-Seq data collected at multiple time points.
View all literature mentionsHarmony (software resource)
RRID:SCR_022206
Software R package to project cells into shared embedding in which cells group by cell type rather than dataset specific conditions. Harmony simultaneously accounts for multiple experimental and biological factors. Used for integration of single cell data.
View all literature mentionsSeurat (software resource)
RRID:SCR_016341
Software as R package designed for QC, analysis, and exploration of single cell RNA-seq data. Enable users to identify and interpret sources of heterogeneity from single cell transcriptomic measurements, and to integrate diverse types of single cell data.
View all literature mentionsBALB/cJGpt (organism)
RRID:IMSR_GPT:N000020
Mus musculus with name BALB/cJGpt from IMSR.
View all literature mentionsDESeq2 (software resource)
RRID:SCR_015687
Software package for differential gene expression analysis based on the negative binomial distribution. Used for analyzing RNA-seq data for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates.
View all literature mentionsHISAT2 (software resource)
RRID:SCR_015530
Graph-based alignment of next generation sequencing reads to a population of genomes.
View all literature mentionsBeckman Coulter CytoFLEX Flow Cytometer (instrument resource)
RRID:SCR_019627
Flow Cytometer provides performance needed for sensitivity and resolution throughout all configurations.
View all literature mentionsHALO (data processing software)
RRID:SCR_018350
Software image analysis platform for quantitative tissue analysis in digital pathology by Indica Labs. Used for high-throughput, quantitative tissue analysis in oncology, neuroscience, metabolism, toxicology.
View all literature mentionsHEK293T (cell line)
RRID:CVCL_0063
Cell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsRenCa (cell line)
RRID:CVCL_2174
Cell line RenCa is a Cancer cell line with a species of origin Mus musculus
View all literature mentionsCaki-1 (cell line)
RRID:CVCL_0234
Cell line Caki-1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentions769-P (cell line)
RRID:CVCL_1050
Cell line 769-P is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsHK2 (cell line)
RRID:CVCL_YE28
Cell line HK2 is a Spontaneously immortalized cell line with a species of origin Acipenser baerii (Siberian sturgeon)
View all literature mentionsBALB/cJGpt (organism)
RRID:IMSR_GPT:N000020
Mus musculus with name BALB/cJGpt from IMSR.
View all literature mentions
