Title |
CTLA4 Promotes Tyk2-STAT3–Dependent B-cell Oncogenicity
|
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Published in |
Cancer Research, September 2017
|
DOI | 10.1158/0008-5472.can-16-0342 |
Pubmed ID | |
Authors |
Andreas Herrmann, Christoph Lahtz, Toshikage Nagao, Joo Y Song, Wing C Chan, Heehyoung Lee, Chanyu Yue, Thomas Look, Ronja Mülfarth, Wenzhao Li, Kurt Jenkins, John Williams, Lihua E Budde, Stephen Forman, Larry Kwak, Thomas Blankenstein, Hua Yu |
Abstract |
Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is a well-established immune checkpoint for antitumor immune responses. The pro-tumorigenic function of CTLA4 is believed to be limited to T cell inhibition by countering the activity of the T cell co-stimulating receptor CD28. However, as we demonstrate here, there are two additional roles for CTLA4 in cancer, including via CTLA4 overexpression in diverse B cell lymphomas and in melanoma-associated B cells. CTLA4-CD86 ligation recruited and activated the JAK family member Tyk2, resulting in STAT3 activation and expression of genes critical for cancer immunosuppression and tumor growth and survival. CTLA4 activation resulted in lymphoma cell proliferation and tumor growth, whereas silencing or antibody-blockade of CTLA4 in B cell lymphoma tumor cells in the absence of T cells inhibits tumor growth. This inhibition was accompanied by reduction of Tyk2/STAT3 activity, tumor cell proliferation, and induction of tumor cell apoptosis. The CTLA4-Tyk2-STAT3 signal pathway was also active in tumor-associated non-malignant B cells in mouse models of melanoma and lymphoma. Overall, our results show how CTLA4 induced immune suppression occurs primarily via an intrinsic STAT3 pathway and that CTLA4 is critical for B cell lymphoma proliferation and survival. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 1 | 25% |
Unknown | 3 | 75% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 3 | 75% |
Scientists | 1 | 25% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 32 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Master | 8 | 25% |
Researcher | 5 | 16% |
Student > Doctoral Student | 3 | 9% |
Student > Ph. D. Student | 3 | 9% |
Other | 2 | 6% |
Other | 3 | 9% |
Unknown | 8 | 25% |
Readers by discipline | Count | As % |
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Biochemistry, Genetics and Molecular Biology | 11 | 34% |
Agricultural and Biological Sciences | 3 | 9% |
Medicine and Dentistry | 3 | 9% |
Immunology and Microbiology | 3 | 9% |
Pharmacology, Toxicology and Pharmaceutical Science | 1 | 3% |
Other | 3 | 9% |
Unknown | 8 | 25% |