Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold

David W. Vredevoogd; Thomas Kuilman; Maarten A. Ligtenberg; Julia Boshuizen; Kelly E. Stecker; Beaunelle de Bruijn; Oscar Krijgsman; Xinyao Huang; Juliana C.N. Kenski; Ruben Lacroix; Riccardo Mezzadra; Raquel Gomez-Eerland; Mete Yildiz; Ilknur Dagidir; Georgi Apriamashvili; Nordin Zandhuis; Vincent van der Noort; Nils L. Visser; Christian U. Blank; Maarten Altelaar; Ton N. Schumacher; Daniel S. Peeper

doi:10.1016/j.cell.2019.06.014

Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold

David W. Vredevoogd, Thomas Kuilman, Maarten A. Ligtenberg, Julia Boshuizen, Kelly E. Stecker, Beaunelle de Bruijn, Oscar Krijgsman, Xinyao Huang, Juliana C.N. Kenski, Ruben Lacroix, Riccardo Mezzadra, Raquel Gomez-Eerland, Mete Yildiz, Ilknur Dagidir, Georgi Apriamashvili, Nordin Zandhuis, Vincent van der Noort, Nils L. Visser, Christian U. Blank, Maarten AltelaarTon N. Schumacher, Daniel S. Peeper^*

^*Corresponding author for this work

Netherlands Cancer Institute

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

New opportunities are needed to increase immune checkpoint blockade (ICB) impact for cancer patients. A genome-wide CRISPR/Cas9 screen uncovered several hits in the TNF pathway sensitizing tumor cells to T cell elimination. TNF antitumor activity was generally limited in tumors at baseline and in ICB non-responders, correlating with its low abundance. Selective inactivation of TNF signaling lowered melanoma and lung cancer thresholds to low TNF levels, thereby increasing tumor susceptibility to T cell attack and augmenting benefit from anti-PD-1 treatment.

Original language	English
Pages (from-to)	585-599.e15
Journal	Cell
Volume	178
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2019.06.014
Publication status	Published - 25 Jul 2019

Keywords

birinapant
immune checkpoint blockade
immunotherapy
lung cancer
melanoma
TNF
TRAF2

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10.1016/j.cell.2019.06.014

1-s2.0-S0092867419306774-mainFinal published version, 3.85 MBLicence: Taverne

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Vredevoogd, D. W., Kuilman, T., Ligtenberg, M. A., Boshuizen, J., Stecker, K. E., de Bruijn, B., Krijgsman, O., Huang, X., Kenski, J. C. N., Lacroix, R., Mezzadra, R., Gomez-Eerland, R., Yildiz, M., Dagidir, I., Apriamashvili, G., Zandhuis, N., van der Noort, V., Visser, N. L., Blank, C. U., ... Peeper, D. S. (2019). Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold. Cell, 178(3), 585-599.e15. https://doi.org/10.1016/j.cell.2019.06.014

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title = "Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold",

abstract = "New opportunities are needed to increase immune checkpoint blockade (ICB) impact for cancer patients. A genome-wide CRISPR/Cas9 screen uncovered several hits in the TNF pathway sensitizing tumor cells to T cell elimination. TNF antitumor activity was generally limited in tumors at baseline and in ICB non-responders, correlating with its low abundance. Selective inactivation of TNF signaling lowered melanoma and lung cancer thresholds to low TNF levels, thereby increasing tumor susceptibility to T cell attack and augmenting benefit from anti-PD-1 treatment.",

keywords = "birinapant, immune checkpoint blockade, immunotherapy, lung cancer, melanoma, TNF, TRAF2",

author = "Vredevoogd, {David W.} and Thomas Kuilman and Ligtenberg, {Maarten A.} and Julia Boshuizen and Stecker, {Kelly E.} and {de Bruijn}, Beaunelle and Oscar Krijgsman and Xinyao Huang and Kenski, {Juliana C.N.} and Ruben Lacroix and Riccardo Mezzadra and Raquel Gomez-Eerland and Mete Yildiz and Ilknur Dagidir and Georgi Apriamashvili and Nordin Zandhuis and {van der Noort}, Vincent and Visser, {Nils L.} and Blank, {Christian U.} and Maarten Altelaar and Schumacher, {Ton N.} and Peeper, {Daniel S.}",

year = "2019",

month = jul,

day = "25",

doi = "10.1016/j.cell.2019.06.014",

language = "English",

volume = "178",

pages = "585--599.e15",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "3",

}

Vredevoogd, DW, Kuilman, T, Ligtenberg, MA, Boshuizen, J, Stecker, KE, de Bruijn, B, Krijgsman, O, Huang, X, Kenski, JCN, Lacroix, R, Mezzadra, R, Gomez-Eerland, R, Yildiz, M, Dagidir, I, Apriamashvili, G, Zandhuis, N, van der Noort, V, Visser, NL, Blank, CU, Altelaar, M, Schumacher, TN & Peeper, DS 2019, 'Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold', Cell, vol. 178, no. 3, pp. 585-599.e15. https://doi.org/10.1016/j.cell.2019.06.014

TY - JOUR

T1 - Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold

AU - Vredevoogd, David W.

AU - Kuilman, Thomas

AU - Ligtenberg, Maarten A.

AU - Boshuizen, Julia

AU - Stecker, Kelly E.

AU - de Bruijn, Beaunelle

AU - Krijgsman, Oscar

AU - Huang, Xinyao

AU - Kenski, Juliana C.N.

AU - Lacroix, Ruben

AU - Mezzadra, Riccardo

AU - Gomez-Eerland, Raquel

AU - Yildiz, Mete

AU - Dagidir, Ilknur

AU - Apriamashvili, Georgi

AU - Zandhuis, Nordin

AU - van der Noort, Vincent

AU - Visser, Nils L.

AU - Blank, Christian U.

AU - Altelaar, Maarten

AU - Schumacher, Ton N.

AU - Peeper, Daniel S.

PY - 2019/7/25

Y1 - 2019/7/25

N2 - New opportunities are needed to increase immune checkpoint blockade (ICB) impact for cancer patients. A genome-wide CRISPR/Cas9 screen uncovered several hits in the TNF pathway sensitizing tumor cells to T cell elimination. TNF antitumor activity was generally limited in tumors at baseline and in ICB non-responders, correlating with its low abundance. Selective inactivation of TNF signaling lowered melanoma and lung cancer thresholds to low TNF levels, thereby increasing tumor susceptibility to T cell attack and augmenting benefit from anti-PD-1 treatment.

AB - New opportunities are needed to increase immune checkpoint blockade (ICB) impact for cancer patients. A genome-wide CRISPR/Cas9 screen uncovered several hits in the TNF pathway sensitizing tumor cells to T cell elimination. TNF antitumor activity was generally limited in tumors at baseline and in ICB non-responders, correlating with its low abundance. Selective inactivation of TNF signaling lowered melanoma and lung cancer thresholds to low TNF levels, thereby increasing tumor susceptibility to T cell attack and augmenting benefit from anti-PD-1 treatment.

KW - birinapant

KW - immune checkpoint blockade

KW - immunotherapy

KW - lung cancer

KW - melanoma

KW - TNF

KW - TRAF2

UR - http://www.scopus.com/inward/record.url?scp=85069738521&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2019.06.014

DO - 10.1016/j.cell.2019.06.014

M3 - Article

C2 - 31303383

AN - SCOPUS:85069738521

SN - 0092-8674

VL - 178

SP - 585-599.e15

JO - Cell

JF - Cell

IS - 3

ER -

Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold

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Keywords

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