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Trp53 Inactivation in the Tumor Microenvironment Promotes Tumor Progression by Expanding the Immunosuppressive Lymphoid-like Stromal Network

Gang Guo, Luis Marrero, Paulo Rodriguez, Luis Del Valle, Augusto Ochoa and Yan Cui
Gang Guo
Authors' Affiliations: Stanley Scott Cancer Center; and Departments of Microbiology, Immunology, and Parasitology, and Pathology, Louisiana State University Medical Center, New Orleans, Louisiana
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Luis Marrero
Authors' Affiliations: Stanley Scott Cancer Center; and Departments of Microbiology, Immunology, and Parasitology, and Pathology, Louisiana State University Medical Center, New Orleans, Louisiana
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Paulo Rodriguez
Authors' Affiliations: Stanley Scott Cancer Center; and Departments of Microbiology, Immunology, and Parasitology, and Pathology, Louisiana State University Medical Center, New Orleans, LouisianaAuthors' Affiliations: Stanley Scott Cancer Center; and Departments of Microbiology, Immunology, and Parasitology, and Pathology, Louisiana State University Medical Center, New Orleans, Louisiana
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Luis Del Valle
Authors' Affiliations: Stanley Scott Cancer Center; and Departments of Microbiology, Immunology, and Parasitology, and Pathology, Louisiana State University Medical Center, New Orleans, LouisianaAuthors' Affiliations: Stanley Scott Cancer Center; and Departments of Microbiology, Immunology, and Parasitology, and Pathology, Louisiana State University Medical Center, New Orleans, Louisiana
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Augusto Ochoa
Authors' Affiliations: Stanley Scott Cancer Center; and Departments of Microbiology, Immunology, and Parasitology, and Pathology, Louisiana State University Medical Center, New Orleans, Louisiana
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Yan Cui
Authors' Affiliations: Stanley Scott Cancer Center; and Departments of Microbiology, Immunology, and Parasitology, and Pathology, Louisiana State University Medical Center, New Orleans, LouisianaAuthors' Affiliations: Stanley Scott Cancer Center; and Departments of Microbiology, Immunology, and Parasitology, and Pathology, Louisiana State University Medical Center, New Orleans, Louisiana
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DOI: 10.1158/0008-5472.CAN-12-3810
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Abstract

Inactivation of the tumor suppressor p53 through somatic mutations, observed in 50% of human cancers, is one of the leading causes of tumorigenesis. Clinical and experimental evidence also reveals that p53 mutations sometimes occur in tumor-associated fibroblasts, which correlate with an increased rate of metastases and poor prognosis, suggesting that p53 dysfunction in the tumor microenvironment (TME) favors tumor establishment and progression. To understand the impact of p53 inactivation in the TME in tumor progression, we compared the growth of subcutaneously inoculated B16F1 melanoma in p53null and wild-type (WT) mice. Interestingly, tumor growth in p53null mice was greatly accelerated, correlating with marked increases in CD11b+Gr-1+ myeloid-derived suppressor cells (MDSC), FoxP3+ regulatory T cells, and a loss of effector function, compared with those in WT mice. This augmented immunotolerant TME in p53null mice was associated with a marked expansion of a specialized stromal network in the tumor and spleen. These stromal cells expressed markers of fibroblastic reticular cells of lymphoid organs and were readily expanded in culture from p53null, but not WT, mice. They produced high levels of inflammatory cytokines/chemokines and immunosuppressive molecules, thereby enhancing MDSC differentiation. Furthermore, they significantly accelerated tumor progression in WT mice when co-injected with B16F1. Together, our results show that tumor-stroma interaction in hosts with dysfunctional p53 exacerbates immunosuppression by expanding the lymphoid-like stromal network that enhances MDSC differentiation and tumor progression. Cancer Res; 73(6); 1–8. ©2012 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received October 1, 2012.
  • Revision received November 30, 2012.
  • Accepted December 17, 2012.
  • ©2012 American Association for Cancer Research.
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Published OnlineFirst March 6, 2013
doi: 10.1158/0008-5472.CAN-12-3810

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Trp53 Inactivation in the Tumor Microenvironment Promotes Tumor Progression by Expanding the Immunosuppressive Lymphoid-like Stromal Network
Gang Guo, Luis Marrero, Paulo Rodriguez, Luis Del Valle, Augusto Ochoa and Yan Cui
Cancer Res March 6 2013 DOI: 10.1158/0008-5472.CAN-12-3810

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Trp53 Inactivation in the Tumor Microenvironment Promotes Tumor Progression by Expanding the Immunosuppressive Lymphoid-like Stromal Network
Gang Guo, Luis Marrero, Paulo Rodriguez, Luis Del Valle, Augusto Ochoa and Yan Cui
Cancer Res March 6 2013 DOI: 10.1158/0008-5472.CAN-12-3810
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