title: Trp53 inactivation in the tumor microenvironment promotes tumor progression by expanding the immunosuppressive lymphoid-like stromal network.
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 p53(null) and wild-type (WT) mice. Interestingly, tumor growth in p53(null) 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 p53(null) 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 p53(null), 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.
authors: Stanley Scott Cancer Center, Louisiana State University Medical Center, New Orleans, Louisiana, USA.
authors: Gang
authors: G
authors: Guo
authors: Luis
authors: L
authors: Marrero
authors: Paulo
authors: P
authors: Rodriguez
authors: Luis
authors: L
authors: Del Valle
authors: Augusto
authors: A
authors: Ochoa
authors: Yan
authors: Y
authors: Cui
mesh_terms: D000818:Animals; D018450:Disease Progression; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008546:Melanoma, Experimental / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059016:Tumor Microenvironment; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology
chemical_list: D016159:Tumor Suppressor Protein p53