CD4+ T Cells Contribute to the Remodeling of the Microenvironment Required for Sustained Tumor Regression upon Oncogene Inactivation
Open accessAbstract
Oncogene addiction is thought to occur cell autonomously. Immune effectors are implicated in the initiation and restraint of tumorigenesis, but their role in oncogene inactivation-mediated tumor regression is unclear. Here, we show that an intact immune system, specifically CD4(+) T cells, is required for the induction of cellular senescence, shutdown of angiogenesis, and chemokine expression resulting in sustained tumor regression upon inactivation of the MYC or BCR-ABL oncogenes in mouse models of T cell acute lymphoblastic lymphoma and pro-B cell leukemia, respectively. Moreover, immune effectors knocked out for thrombospondins failed to induce sustained tumor regression. Hence, CD4(+) T cells are required for the remodeling of the tumor microenvironment through the expression of chemokines, such as thrombospondins, in order to elicit oncogene addiction.
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Depletion of MYC in a mouse subcutaneous T-ALL model results in sustained tumour regression associated with senescence and apoptosis, where adaptive immune response involving CD4+ T cells is required for senescence induction and sustained regression, but not apoptosis induction.
“the depletion of MYC in a mouse subcutaneous transplantation model of T cell acute lymphoblastic lymphoma (T-ALL), which carries tetracycline regulated MYC transgene, results in sustained tumour regression associated with senescence and apoptosis, where an adaptive immune response (involving CD4 + T cells in particular) was required for senescence induction and sustained tumour regression, but not”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [116]
In a model with an inducible BCR-ABL allele in blood-forming tissue, suppressing BCR-ABL causes pro-B cell leukemia regression.
“| | hematopoietic system | BCR-ABL suppression | Regression of pro-B cell leukemia | 116 | | | |”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [116]
In a haematopoietic system model, suppressing MYC causes lymphoma regression.
“| | haematopoietic system | MYC suppression | lymphoma | 116 | | | |”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [116]
In a new p16-monitor mouse model, stromal senescence correlates closely and generally with early neoplastic events.
“This study shows a close and general correlation between stromal senescence and early neoplastic events in a new p16-monitor mouse model.”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [116]
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References 77 · Cited by 339
Research works printed but not linked: 2
- Kazerounian S Yee KO Lawler J 2008 Thrombospondins in cancer Cell Mol Life Sci 65 700 712 18193162 PMC2752021
- Shchors K Shchors E Rostker F Lawlor ER Brown-Swigart L Evan GI 2006 q Genes & development 20 2527 2538 16980582 PMC1578676
- Authors
- Rakhra, K., Bachireddy, P., Zabuawala, T., Zeiser, R., Xu, L., Kopelman, A., Fan, A. C., Yang, Q., Braunstein, L., Crosby, E., Ryeom, S., & Felsher, D. W.
- Affiliations
- Stanford Medicine (US)
- Boston Children's Hospital (US)
- University of Pennsylvania (US)
- Corresponding author
- Felsher, Dean W.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2010-11
- Volume
- 18
- Issue
- 5
- Pages
- 485-498
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC2991103
- OpenAlex
- W2162981791
- Cited by
- 339
- References
- 77
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 15 · 2023: 20 · 2022: 19 · 2021: 19 · 2020: 22 · 2019: 22 · 2018: 19 · 2017: 23 · 2016: 21 · 2015: 19 · 2014: 22 · 2013: 31 · 2012: 41
- FWCI
- 13.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (P50CA114747, R01CA105102, K23CA140722, U56CA112973, CA 114747, P01CA034233, R56CA118374, CA112973, R01CA089305, R01CA118374)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- CD4+ T cells, tumor microenvironment remodeling, tumor regression, oncogene addiction, oncogene inactivation, c-Myc, BCR-ABL, T-cell acute lymphoblastic lymphoma, cellular senescence, angiogenesis, thrombospondin, chemokines
- MeSH terms
- Animals, Immunosuppressive Agents, Leukemia, Experimental, Mice, Transgenic, Neoplasms, Neovascularization, Pathologic, Oncogenes, Remission Induction, CD4-Positive T-Lymphocytes, Gene Expression Regulation, Neoplastic, Fusion Proteins, bcr-abl, Proto-Oncogene Proteins c-myc, Cyclosporine, Cellular Senescence, Apoptosis, Chemokines, Thrombospondin 1, Gene Silencing, Cell Proliferation, Mice, Tumor Microenvironment
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