Supplementary Figures 1-6 PDF file - 340K, Supplemental Figure S1. Trp53 inactivation in hosts results in an augmented immunotolerant tumor microenvironment. Supplemental Figure S2. Trp53 inactivation in B16F1 tumor bearing hosts does not impose significant effects on the splenic effector T cell function as compared with those in WT tumor bearing mice. Supplemental Figure S3. Tumor associated MDSCs from WT and p53null mice share similar phenotype and suppressor function on per cell basis. Supplemental Figure S4. Analyses of cell surface marker expression profile of MEF from p53null mice. Supplemental Figure S5. Differential differentiation of BM-MDSCs from WT and p53null mice stimulated by different myeloipoietic cytokines. Supplemental Figure S6. SPSCs from p53null mice enhanced BM-MDSCs differentiation in part by suppressing apoptosis of myeloid precursors.
ARTICLE 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); 1668–75. ©2012 AACR.
