Human NK Cells Are Alerted to Induction of p53 in Cancer Cells by Upregulation of the NKG2D Ligands ULBP1 and ULBP2
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Abstract
Natural killer (NK) cells are immune cells sensing and eliminating foreign, stressed, transformed, and senescent cells through specialized surface receptors, such as NKG2D, that interacts with several virus- or stress-inducible ligands, including ULBP1 and -2, which are expressed on target cell surfaces. For example, induction of DNA damage or cellular senescence pathways in tumor cells led to upregulation of NKG2D ligands that activate NK cells. Although, both pathways activate p53, the relationship of p53 activation to upregulation of NKG2D ligands has not been addressed. In this study, we report that induction of wild-type p53, but not mutant p53, strongly upregulated mRNA and cell surface expression of ULBP1 and -2, whereas expression of other NK cell ligands was not affected. We defined intronic p53-responsive elements in these two novel p53 target genes. Coculture of wild-type p53-induced human tumor cells with primary human NK cells enhanced NKG2D-dependent degranulation and IFN-γ production by NK cells. Accordingly, treatment of certain wild-type p53-expressing tumor cell lines with the p53-reactivating small molecular compound RITA resulted in upregulation of ULBP2 mRNA and cell surface protein expression. Taken together, our findings define the involvement of p53 in the regulation of specific NKG2D ligands that enhance NK cell–mediated target recognition. One implication of our work is that activating p53 after adoptive transfer of NK cells might constitute an effective combinatorial strategy of NK cell–based immunochemotherapy in cancers in which wild-type p53 function is preserved. Cancer Res; 71(18); 5998–6009. ©2011 AACR.
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Some missense mutant proteins can lose the transcriptional effects of wild-type genes, such as keeping PDL1 expression low, making cancer cells more susceptible to cytotoxic T cells and NK cells, limiting the immune system's ability to attack cancer cells.
“Some missense mutant proteins can lose the transcriptional effects of wild-type genes, such as keeping PDL1 expression levels low, thereby making cancer cells more susceptible to cytotoxic T cells and NK cells, limiting the immune system’s ability to attack cancer cells.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [613]
Activating wild-type proteins can increase IFNγ signaling and sensitize tumors to immune checkpoint inhibitors, whereas corresponding mutant proteins can reduce the efficacy of immune checkpoint inhibitors.
“On the other hand, activating wild-type proteins can increase IFNγ signaling and sensitize tumors to immune checkpoint inhibitors, whereas corresponding mutant proteins can reduce the efficacy of immune checkpoint inhibitors.612–614”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [613]
The status of genes can influence tumor cells through the impact of wild-type gene loss and through their effects on the tumor immune microenvironment.
“In brief, the status of genes can influence tumor cells not only through the impact of wild-type gene loss but also through their effects on the TIME.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [613]
Pharmacological reactivation of p53 in specific cell lines can stimulate the expression of ULPB2, a ligand for human NKG2D.
“In contrast, two studies reported that pharmacological reactivation of p53 in specific cell lines can stimulate the expression of ULPB2, a ligand for human NKG2D (Li et al., 2011; Textor et al., 2011).”
From p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells (2013) · cites this paper as Textor et al., 2011
Pharmacological p53 reactivation upregulates NKALs.
“Additional immunostimulatory effects linked to pharmacological p53 reactivation in cancer cells include (but are not limited to) (1) downregulation of immunomodulatory cytokines linked to tumor progression, such as IL6 (Sahin et al., 2020); (2) upregulation of NKALs (Textor et al., 2011); and (3) establishment of cellular senescence linked to an immunostimulatory SASP that favors the recruitment”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Textor et al., 2011
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- Authors
- Textor, S., Fiegler, N., Arnold, A., Porgador, A., Hofmann, T. G., & Cerwenka, A.
- Affiliations
- Ben-Gurion University of the Negev (IL)
- Corresponding author
- Cerwenka, Adelheid
- Venue
- Cancer Research
- Published
- 2011-09-13
- Volume
- 71
- Issue
- 18
- Pages
- 5998-6009
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2123143632
- Cited by
- 221
- References
- 36
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 18 · 2023: 13 · 2022: 18 · 2021: 13 · 2020: 19 · 2019: 11 · 2018: 12 · 2017: 10 · 2016: 15 · 2015: 15 · 2014: 14 · 2013: 20 · 2012: 13
- FWCI
- 7.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- natural killer cells, NKG2D ligands, ULBP1, ULBP2, p53, wild-type p53, p53 target genes, p53 response elements, NK cell cytotoxicity, interferon-gamma, RITA, p53 reactivation
- MeSH terms
- Carcinoma, Non-Small-Cell Lung, Furans, Humans, Introns, Killer Cells, Natural, Lung Neoplasms, RNA, Messenger, Up-Regulation, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Intercellular Signaling Peptides and Proteins, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, NK Cell Lectin-Like Receptor Subfamily K, GPI-Linked Proteins
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