Trp53 inactivation in the tumor microenvironment promotes tumor progression by enhancing MDSC differentiation (P2073)

Abstract

Abstract Inactivation of the tumor suppressor p53 is one of the leading causes of cancer as p53 inactivation via somatic mutations occurs in 50% of human cancers and sometimes in other cells of the tumor microenvironment (TME). Recent studies by our laboratory and others showed that innate and adaptive immunities are skewed towards pro-inflammation in hosts lacking p53 function. As chronic inflammation plays a vital role in tumor initiation, progression, and metastases, we hypothesized that p53 inactivation in the TME favors tumorigenesis by promoting inflammation. In this study, we compared the growth of subcutaneously inoculated B16F1 melanoma in p53null and WT mice. Tumor growth in p53null mice was greatly accelerated, correlating with marked increases in CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs), FoxP3+ regulatory T cells, and a loss of effector function, compared with those in WT mice. This augmented immunotolerance in tumor bearing p53null mice was associated with an enhanced MDSC proliferation, an increased frequency of myeloid progenitors in the peripheral lymphoid tissues, and a marked elevation of serum inflammatory cytokines/chemokines, compared with those of WT mice. Together, these results support our hypothesis and reveal a previously unappreciated function for p53 in maintaining an immunological microenvironment that suppresses tumor initiation and progression.