p53 Inactivation in the Tumor Microenvironment Promotes Tumor Progression via Immunosuppressive Lymphoid-like Stromal Network
Inactivation of the tumor suppressor p53 through somatic mutations is observed in approximately half of cancers. The finding that p53 mutations sometimes occur in tumor-associated fibroblasts and are correlated with an increased rate of metastases and poor prognosis suggests that p53 dysfunction in the tumor microenvironment promotes tumor establishment and progression.
In studying the potential role of p53 inactivation in the tumor microenvironment, Guo and colleagues compared the growth of subcutaneously inoculated B16F1 melanoma in p53-null and wild-type mice. Tumor growth was markedly accelerated in p53-nullmice and was correlated with marked increases in CD11b+Gr-1+ myeloid-derived suppressor cells, FoxP3+ regulatory T cells, and loss of effector function compared with wild-type mice.
The increased immunotolerance of the tumor microenvironment was associated with 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 wild-type mice. The cells produced high levels of inflammatory cytokines/chemokines and immunosuppressive molecules that enhanced myeloid-derived suppressor cell differentiation; further, the cells significantly accelerated tumor progression in wild-type mice when injected along with B16F1.
The investigators concluded, “Together, our results show that tumor-stroma interaction in hosts with dysfunctional p53 exacerbates immunosuppression by expanding the lymphoid-like stromal network that enhances [myeloid-derived suppressor cell] differentiation and tumor progression.” ■
Guo G, Marrero L, Rodriguez P, et al: Trp53 inactivation in the tumor microenvironment promotes tumor progression by expanding the immunosuppressive lymphoid-like stromal network. Cancer Res 73:1668-1675, 2013.