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Publication

Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1+ T lymphocyte niches through a feed-forward loop.

Cancer cell | 2022

The lack of T cell infiltrates is a major obstacle to effective immunotherapy in cancer. Conversely, the formation of tumor-associated tertiary-lymphoid-like structures (TA-TLLSs), which are the local site of humoral and cellular immune responses against cancers, is associated with good prognosis, and they have recently been detected in immune checkpoint blockade (ICB)-responding patients. However, how these lymphoid aggregates develop remains poorly understood. By employing single-cell transcriptomics, endothelial fate mapping, and functional multiplex immune profiling, we demonstrate that antiangiogenic immune-modulating therapies evoke transdifferentiation of postcapillary venules into inflamed high-endothelial venules (HEVs) via lymphotoxin/lymphotoxin beta receptor (LT/LTβR) signaling. In turn, tumor HEVs boost intratumoral lymphocyte influx and foster permissive lymphocyte niches for PD1- and PD1+TCF1+ CD8 T cell progenitors that differentiate into GrzB+PD1+ CD8 T effector cells. Tumor-HEVs require continuous CD8 and NK cell-derived signals revealing that tumor HEV maintenance is actively sculpted by the adaptive immune system through a feed-forward loop.

Pubmed ID: 36423635 RIS Download

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Associated grants

  • Agency: NCI NIH HHS, United States
    Id: R01 CA201537

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

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Alexa Fluor 488-AffiniPure Donkey Anti-Goat IgG (H+L) (min X Ck,GP,Sy Hms,Hrs,Hu,Ms,Rb,Rat Sr Prot) (antibody)

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Donkey anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 647 (antibody)

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Anti-ERG antibody (antibody)

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This monoclonal targets Mouse LYMPHOTOXIN BETA RECEPTOR

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InVivoPlus anti-mouse CTLA-4 (CD152) (antibody)

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This monoclonal targets CTLA-4 (CD152)

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InVivoPlus anti-mouse PD-L1 (B7-H1) (antibody)

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This monoclonal targets PD-L1 (B7-H1)

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InVivoPlus anti-mouse VEGFR-2 (antibody)

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This monoclonal targets VEGFR-2

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InVivoPlus anti-mouse IFNγ (antibody)

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This monoclonal targets IFNγ

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InVivoPlus anti-mouse NK1.1 (antibody)

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This monoclonal targets NK1.1

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rat IgG2b I sotype control (antibody)

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This isotype control targets KLH

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anti-mouse CD8α (antibody)

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This monoclonal targets CD8α

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anti-mouse CD4 (antibody)

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InVivoPlus anti-mouse CSF1R (CD115) (antibody)

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This monoclonal targets CSF1R (CD115)

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Rat Anti-CD16 / CD32 Monoclonal Antibody, Unconjugated, Clone 2.4G2 (antibody)

RRID:AB_394657

This monoclonal targets CD16 / CD32

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Perforin antibody [5B10] (antibody)

RRID:AB_2042606

This monoclonal targets Human Perforin

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Human/Mouse Desmin Affinity Purified Polyclonal Ab (antibody)

RRID:AB_2092419

This polyclonal targets Human/Mouse Desmin Affinity Purified Ab

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Brilliant Violet 421(TM) anti-mouse TNF-alpha (antibody)

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This monoclonal targets TNF-alpha

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Brilliant Violet 785(TM) anti-mouse CD19 (antibody)

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PE/Cyanine5 anti-mouse TCR beta chain (antibody)

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This monoclonal targets TCR beta chain

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Purified KI67 (MKI67) mouse monoclonal antibody,clone UMAB107 (antibody)

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Ki-67 (D3B5) Rabbit Antibody (Alexa Fluor 488 Conjugate) (antibody)

RRID:AB_2687824

This monoclonal targets Ki-67 (D3B5)

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Alexa Fluor(R) 700 anti-mouse Ki-67 (antibody)

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Brilliant Violet 650(TM) anti-mouse/rat XCR1 (antibody)

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TCF7-human - ENCODE validation data (antibody)

RRID:AB_2199302

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Goat Anti-Human Tim-3 Polyclonal antibody, Unconjugated (antibody)

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This polyclonal targets Human TIM-3

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Recombinant Anti-TIM 3 antibody [EPR22241] (antibody)

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Brilliant Violet 605(TM) anti-mouse CD366 (Tim-3) (antibody)

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CD25 (IL-2 Receptor α) (antibody)

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ROR gamma (t) Monoclonal Antibody (B2D), PE, eBioscience (antibody)

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APC/Fire(TM) 750 anti-mouse/human CD44 (antibody)

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Brilliant Violet 570(TM) anti-mouse/human CD44 (antibody)

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Alexa Fluor(R) 700 anti-mouse I-A/I-E (antibody)

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Purified anti-mouse NK-1.1 (antibody)

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Brilliant Violet 421(TM) anti-mouse CD11c (antibody)

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Goat Anti-Mouse Pd-1 Polyclonal antibody, Unconjugated (antibody)

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PD-1 (D7D5W) XP® Rabbit mAb (Mouse Specific) (Alexa Fluor® 555 Conjugate) (antibody)

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PD-1 (D4W2J) XP® (antibody)

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Brilliant Violet 711(TM) anti-mouse CD279 (PD-1) (antibody)

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Goat Anti-Mouse Granzyme b Polyclonal antibody, Biotin Conjugated (antibody)

RRID:AB_2114416

This polyclonal targets Mouse Granzyme B

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PE/Dazzle(TM) 594 anti-human/mouse Granzyme B Recombinant (antibody)

RRID:AB_2728382

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Granzyme B Monoclonal Antibody (NGZB), PE, eBioscience (antibody)

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CD45 (antibody)

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APC anti-mouse CD45 (antibody)

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FOXP3 Monoclonal Antibody (FJK-16s), Biotin, eBioscience (antibody)

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FoxP3 Antibody, anti-mouse, APC, REAfinity™ (antibody)

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PE/Cyanine7 anti-mouse CD172a (SIRPalpha) (antibody)

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PE/Cyanine7 anti-mouse lymphotoxin beta receptor (LTbetaR) (antibody)

RRID:AB_2728152

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APC anti-mouse CD3 (antibody)

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Brilliant Violet 570(TM) anti-mouse CD3 (antibody)

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Brilliant Violet 650(TM) anti-mouse CD3 (antibody)

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PE/Dazzle(TM) 594 anti-mouse CD64 (FcgammaRI) (antibody)

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Brilliant Violet 510(TM) anti-mouse/human CD11b (antibody)

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BUV496 Rat Anti-Mouse CD4 (antibody)

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Alexa Fluor(R) 647 anti-mouse CD4 (antibody)

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CD8-alpha (C8/144B) (antibody)

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CD8a Monoclonal Antibody (4SM15), eBioscience (antibody)

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Brilliant Violet 421(TM) anti-mouse CD8a (antibody)

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BUV805 Rat Anti-Mouse CD8a (antibody)

RRID:AB_2716856

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APC anti-mouse CD8a (antibody)

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Anti-Human Von Willebrand Factor Antibody (antibody)

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CD106 (VCAM-1) Monoclonal Antibody (429), eBioscience (antibody)

RRID:AB_467419

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CD62P (P-Selectin) (antibody)

RRID:AB_2738366

This monoclonal targets CD62P (P-Selectin)

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MS CD62E PURE MAB 0.5MG 10E9.6 (antibody)

RRID:AB_2186705

This monoclonal targets CD62E (E-Selectin)

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MECA-79 (MECA-79) (antibody)

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Alexa Fluor(R) 647 anti-mouse/human PNAd (antibody)

RRID:AB_2783060

This monoclonal targets PNAd

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High Endothelial Venule Marker Monoclonal Antibody (MECA-79), Alexa Fluor™ 488, eBioscience (antibody)

RRID:AB_10804391

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Armenian Hamster Anti-CD54 Monoclonal Antibody, Unconjugated, Clone 300 (antibody)

RRID:AB_393582

This monoclonal targets CD54 (ICAM-1)

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APC anti-mouse CD31 (antibody)

RRID:AB_312905

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Armenian hamster Anti-PECAM-1 (CD31, gpIIa) Monoclonal antibody, Unconjugated, Clone 2h8 (antibody)

RRID:AB_94207

This monoclonal targets PECAM-1 (CD31, gpIIa)

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Anti-CD31 antibody (antibody)

RRID:AB_726362

This polyclonal targets CD31

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Alexa Fluor(R) 647 anti-mouse/human CD45R/B220 (antibody)

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