NK cell–mediated cytotoxicity contributes to tumor control by a cytostatic drug combination
Open accessAbstract
Small molecules spark NK cell response: Immunotherapy is a powerful treatment for certain cancers. Yet for those patients that do not respond, simultaneous strategies that mobilize the immune system and directly target malignant cells may be more effective. Ruscetti et al. report that combining two clinically approved cancer drugs promoted immune surveillance and killing of KRAS-mutant lung tumors in mice (see the Perspective by Cornen and Vivier). The two small molecules—a mitogen-activated protein kinase inhibitor and a cyclin-dependent kinase 4/6 inhibitor—induced natural killer (NK) cell recruitment and elimination of senescent lung cancer cells, which did not occur when either agent was used alone. Science , this issue p. 1416 ; see also p. 1355
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Immune surveillance and clearance of senescent cells is necessary to limit tumorigenesis in premalignant lesions and after cancer therapy.
“The surveillance and clearance of senescent cells by the immune system is necessary in order to limit tumorigenesis in premalignant lesions and following cancer therapy155,156,159.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [159]
In the paper’s discussion of combination-treated KRAS-mutant lung tumors (section labeled Abstract; page unavailable), NK-cell depletion prevented tumor regression and reduced the treatment’s survival benefit, supporting a role for immune clearance after this therapy. The discussion of premalignant cells concerns RB-mediated restraint of proliferation, not a demonstrated need for immune clearance of senescent cells in premalignant lesions. The claim also generalizes beyond the specific therapy and mouse models studied. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRuscetti et al. showed that while palbociclib treatment of lung tumors alone induces features of senescence, its combination with the MEK inhibitor Trametinib (T/P) results in a stronger growth arrest and a more potent SASP.
“Ruscetti et al. (2018) showed that while palbociclib treatment of lung tumors alone induces features of senescence, its combination with the MEK inhibitor Trametinib (T/P) results in a stronger growth arrest and a more potent SASP.”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Ruscetti et al. 2018
The passage on senescence markers (section labeled Abstract; no page given) says only the combination produced significant senescence markers and a durable arrest; it does not establish that palbociclib alone induced features of senescence. The passages on proliferation and SASP expression support the claim that adding trametinib produced stronger growth inhibition and greater SASP-factor expression than either drug alone. (LLM, conf=0.88)
Experimental — accuracy not yet measuredT/P induces senescence in a KRAS-mutant lung cancer model and activates an immunomodulatory SASP, comprised of TNF-α and ICAM1, which promotes NK cell surveillance and tumor regression and prolongs survival.
“Indeed, T/P induces senescence in a KRAS-mutant lung cancer model and activates an immunomodulatory SASP, comprised of TNF-α and intercellular adhesion molecule−1 (ICAM1). This promotes NK cell surveillance and tumor regression and prolongs survival (Ruscetti et al. 2018).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Ruscetti et al. 2018
Combinations of inhibitors of MEK and CDK4/6 potently induced cellular senescence accompanied by NF-κB-driven SASP in a Kras-mutant-driven mouse model of lung cancer.
“Combinations of inhibitors of MEK and CDK4/6 potently induced cellular senescence accompanied by NF- κB- driven SASP in a Kras - mutant- driven mouse model of lung cancer 151 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [151]
In these mice, the SASP components TNFα and ICAM1 subsequently elicited natural killer (NK) cell-mediated immunosurveillance that contributed to tumour regression.
“In these mice, the SASP components TNFα and ICAM1 subsequently elicited natural killer (NK) cell- mediated immunosurveillance that contributed to tumour regression 151 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [151]
Combinatorial interventions aiming to maximize senescence in tumors, such as MEKi plus CDK4/6i, incidentally elicit superior NK-mediated anticancer surveillance.
“Accordingly, combinatorial interventions that aim at maximizing senescence levels in tumors (e.g., MEKi + CDK4/ 6i) incidentally elicit superior NK-mediated anticancer surveillance.188”
From Meta-hallmarks of aging and cancer (2023) · cites this paper as [188]
In preclinical KRAS-driven lung and pancreatic adenocarcinoma models, trametinib and palbociclib synergize to induce a SASP-dependent vascular response that allows immune effector cells to infiltrate tumors.
“trametinib synergizes with palbociclib at inducing a SASP-dependent vascular response that enables tumor infiltration by immune effector cells”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Ruscetti et al., 2018
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- Authors
- Ruscetti, M., Leibold, J., Bott, M. J., Fennell, M., Kulick, A., Salgado, N. R., Chen, C.-C., Ho, Y.-J., Sanchez-Rivera, F. J., Feucht, J., Baslan, T., Tian, S., Chen, H.-A., Romesser, P. B., Poirier, J. T., Rudin, C. M., de Stanchina, E., Manchado, E., Sherr, C. J., & Lowe, S. W.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
- Department of Molecular Pharmacology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Ruscetti, Marcus
- Leibold, Josef
- Bott, Matthew J.
- Lowe, Scott W.
- ORCID
- Venue
- Science
- Published
- 2018-12-21
- Volume
- 362
- Issue
- 6421
- Pages
- 1416-1422
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC6711172
- OpenAlex
- W2903803003
- Cited by
- 415
- References
- 42
- Citations by year
- 2026: 40 · 2025: 62 · 2024: 67 · 2023: 51 · 2022: 64 · 2021: 44 · 2020: 57 · 2019: 28 · 2018: 1
- FWCI
- 13.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (T32-CA160001, K12 CA184746, U54 OD020355 01)
- Howard Hughes Medical Institute (Hanna Gray Fellow)
- National Cancer Institute (PO1 CA129243-06, P30 CA008748 S5)
- Memorial Sloan-Kettering Cancer Center (Center of Experimental Therapeutics, Parker Institute for Cancer Immunotherapy pilot grant, Single Cell Sequencing Initiative)
- American Cancer Society (129040-PF-16-115-01-TBG)
- American Association for Thoracic Surgery (Andrew Morrow Research Scholarship)
- Stand Up To Cancer
- Geoffrey Beene Cancer Research Center
- German Research Foundation
- William C. and Joyce C. O'Neil Charitable Trust
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- natural killer cells, NK cell cytotoxicity, KRAS-mutant lung cancer, MAPK inhibitors, cyclin-dependent kinase 4/6 inhibitors, drug combination therapy, cellular senescence, retinoblastoma protein, senescence-associated secretory phenotype, TNF-α, ICAM-1, tumor surveillance, tumor regression
- MeSH terms
- Aminopyridines, Animals, Antineoplastic Combined Chemotherapy Protocols, Benzimidazoles, Cytotoxicity, Immunologic, Humans, Immunologic Surveillance, Killer Cells, Natural, Lung Neoplasms, Mice, Inbred C57BL, Mutation, Piperazines, Purines, Pyridines, Pyridones, Pyrimidinones, Tumor Necrosis Factor-alpha, Retinoblastoma Protein, Proto-Oncogene Proteins p21(ras), Cellular Senescence, Apoptosis, Intercellular Adhesion Molecule-1, Mitogen-Activated Protein Kinases, Xenograft Model Antitumor Assays, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Mice, Cytostatic Agents, Molecular Targeted Therapy
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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