Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold
Open accessAbstract
New opportunities are needed to increase immune checkpoint blockade (ICB) benefit. Whereas the interferon (IFN)γ pathway harbors both ICB resistance factors and therapeutic opportunities, this has not been systematically investigated for IFNγ-independent signaling routes. A genome-wide CRISPR/Cas9 screen to sensitize IFNγ receptor-deficient tumor cells to CD8 T cell elimination uncovered several hits mapping to the tumor necrosis factor (TNF) pathway. Clinically, we show that TNF antitumor activity is only limited in tumors at baseline and in ICB non-responders, correlating with its low abundance. Taking advantage of the genetic screen, we demonstrate that ablation of the top hit, TRAF2, lowers the TNF cytotoxicity threshold in tumors by redirecting TNF signaling to favor RIPK1-dependent apoptosis. TRAF2 loss greatly enhanced the therapeutic potential of pharmacologic inhibition of its interaction partner cIAP, another screen hit, thereby cooperating with ICB. Our results suggest that selective reduction of the TNF cytotoxicity threshold increases the susceptibility of tumors to immunotherapy.
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Pooled in vivo and in vitro CRISPR-Cas9 based screening have nominated several tumour intrinsic drivers of resistance to immunotherapy, but therapeutic applications of these findings remain limited.
“Pooled in vivo and in vitro CRISPR-Cas9 based screening have nominated several tumour intrinsic drivers of resistance to immunotherapy 4,8-11 , but therapeutic applications of these findings remain limited.”
From Targeting TBK1 to overcome resistance to cancer immunotherapy (2023) · cites this paper as [11]
IFNγ and TNFα are key effector cytokines that contribute to anti-tumour immune responses, and genes associated with IFN and TNF signaling pathways contribute to immune evasion.
“IFN γ and TNF α are key effector cytokines that contribute to anti-tumour immune responses 9,11,27-30 , and genes associated with IFN and TNF signaling pathways contribute to immune evasion 4,9,29 .”
From Targeting TBK1 to overcome resistance to cancer immunotherapy (2023) · cites this paper as [11]
Our findings demonstrate critical interplay between TNFα and IFNγ signaling that can be therapeutically exploited to sensitize tumour cells to immune attack.
“Whereas a key role for TNF α signaling has been demonstrated in immunotherapy-resistant melanoma cell lines devoid of IFN γ signaling 11 , our findings demonstrate critical interplay between TNF α and IFN γ signaling that can be therapeutically exploited to sensitize tumour cells to immune attack.”
From Targeting TBK1 to overcome resistance to cancer immunotherapy (2023) · cites this paper as [11]
TBK1 has been nominated as a candidate immune evasion gene.
“thus it is surprising that TBK1 has been nominated as a candidate immune evasion gene 4,9-11”
From Targeting TBK1 to overcome resistance to cancer immunotherapy (2023) · cites this paper as [11]
The Summary (p. 2) and Discussion (p. 13) describe immune-sensitivity screen hits, particularly TRAF2, but do not nominate TBK1 as an immune-evasion gene. Searches for “TBK1” and “candidate immune evasion gene TBK1” found no passage in our copy addressing that nomination. (LLM, conf=0.72)
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References 74 · Cited by 259
- Authors
- 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., Altelaar, M., Schumacher, T. N., & Peeper, D. S.
- Affiliations
- The Netherlands Cancer Institute (NL)
- Utrecht University (NL)
- Corresponding author
- Peeper, Daniel S.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 178
- Issue
- 3
- Pages
- 585-599.e15
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2956987968
- Cited by
- 259
- References
- 74
- Citations by year
- 2026: 20 · 2025: 40 · 2024: 39 · 2023: 42 · 2022: 37 · 2021: 41 · 2020: 37 · 2019: 3
- FWCI
- 12.30
- Type
- journal article
- Language
- en
- Update notices
- erratum (2020-01-23)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Netherlands Organization for Scientific Research
- VIDI (723.012.102)
- Proteins@Work (184.032.201)
- Dutch Cancer Society (NKI 2014-7241)
- European Research Council
- European Union’s Seventh Framework Programme (FP7/2007–2013)
- ERC (319661 COMBATCANCER)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- TNF-α, immune checkpoint blockade, immunotherapy resistance, TRAF2, cIAP, TNF signaling, interferon-gamma pathway, CRISPR-Cas9 screen, combination immunotherapy
- MeSH terms
- RNA, Guide, CRISPR-Cas Systems, Interferon gamma Receptor, Animals, Humans, Immunotherapy, Interferon-gamma, Male, Mice, Inbred C57BL, Neoplasms, Tumor Necrosis Factor-alpha, Signal Transduction, Apoptosis, Receptors, Interferon, CD8-Positive T-Lymphocytes, Cell Line, Tumor, TNF Receptor-Associated Factor 2, Inhibitor of Apoptosis Proteins, Mice, Kaplan-Meier Estimate, Receptor-Interacting Protein Serine-Threonine Kinases
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