Increasing evidence has linked chronic inflammation to tumor development, progression, and metastases. Clinical and experimental results suggest that chronic inflammation enhances expression of the tumor suppressor p53 leading to its mutations and inactivation. In fact, p53 mutations are observed in 50% of human cancers and are considered to be one of the leading causes of cancer. Moreover, in tumors that maintain normal p53 gene, p53 mutations sometimes occur in cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME), which correlates with an increased rate of metastases and poor prognosis. Although it is well appreciated that immune dysregulation in the TME plays a crucial role in tumorigenesis, whether p53 inactivation immunomodulates the TME and whether the immunological consequence of p53 inactivation plays an integral role in tumorigenesis are still largely unexplored. Since recent studies by our laboratory and others have shown that the immunological environment in p53null hosts is skewed in favor of inflammation, we hypothesized that p53 inactivation in the cellular compartment constituting the TME favors tumor establishment and progression by promoting inflammation. Indeed, our studies showed that inoculated B16-F1 melanoma progressed more rapidly in p53null mice than that in WT mice, which is associated with a marked expansion of the lymphoid-like stromal network and enhanced accumulation of myeloid-derived suppressor cells (MDSC), both of which are immunosuppressive due to their high expression of proinflammatory cytokines and chemokines. Here, we propose to elucidate mechanistically how p53 inactivation enhances inflammatory responses and promotes the development of MDSCs, thereby tumor progression, through the following specific aims: (1) to determine whether tumor-stroma interaction in the tumor microenvironment lacking functional p53 results in the expansion of the lymphoid-like reticular fibroblastic cell (FRC) network, due to highly activated NF-kB pathway, which creates a cytokine milieu and immunological microenvironment strongly favoring MDSC development;(2) to examine whether the augmented MDSC development and tumor progression in p53null hosts are contributed by p53 inactivation enhanced proliferation of myeloid progenitors and lymphoid-like FRC-mediated enhancement of MDSC accumulation;and (3) to determine whether p53 inactivation in fibroblasts and myeloid precursors synergistically enhances chronic inflammation and tumorigenesis in the dextran sulfate sodium (DSS)-induced colon cancer, whereas targeted restoration of p53 in fibroblast or MDSC delays colon cancer development. By focusing on the mechanisms of p53 dysfunction in promoting MDSC development and tumor progression, this application provides novel insights into the immunological mechanism of p53 dysfunction/inactivation in tumorigenesis and new strategies targeting the p53 pathway in the TME that can be implemented to tumor treatment. .

Public Health Relevance

Trp53 inactivation is one of the leading causes of cancer. Interestingly p53 inactivation is also induced in various physiological and pathological conditions by viral infection, oncogene activation, and aging process, some of which have been linked to tumorigenesis. The novel concepts on the immunological mechanism of p53 dysfunction/inactivation in tumorigenesis developed in this project will not only broaden our understanding of the largely unappreciated immunomodulatory function of p53 in tumor suppression, but also provide valuable insights into new strategies targeting the p53 pathway in the tumor microenvironment that can be implemented to new tumor immunotherapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA169133-01A1
Application #
8577716
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Howcroft, Thomas K
Project Start
2013-07-01
Project End
2018-04-30
Budget Start
2013-07-01
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$298,800
Indirect Cost
$91,300
Name
Louisiana State Univ Hsc New Orleans
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112