The role of IL-33 particularly in tumor growth and tumor immunity remains ill defined. We show here that exogenous IL-33 can induce robust antitumor effect through a CD8+ T cell-dependent mechanism. Systemic administration of recombinant IL-33 (rIL-33) alone was sufficient to inhibit growth of established tumors in both transplant and de novo melanoma tumorigenesis models. Notably, in addition to a direct action on CD8+ T cell expansion and IFN-γ production, rIL-33 therapy activated myeloid dendritic cells (mDCs) in tumor-bearing mice, restored antitumor T cell activity and increased antigen cross-presentation within the tumor microenvironment. Furthermore, combination therapy with rIL-33 and agonistic anti-CD40 antibodies demonstrated synergistic antitumor activity. Specifically, MyD88, an essential component of the IL-33 signaling pathway, was required for the IL-33-mediated increase in mDC number and upregulation of costimulatory molecule expression. Importantly, we identified that the IL-33 receptor ST2, MyD88 and STAT1 cooperate to induce costimulatory molecule expression on mDCs in response to rIL-33. Our study has thus revealed a novel IL-33-ST2-MyD88-STAT1 axis that restores mDC activation and maturation in established cancer, and thereby the magnitude of anti-tumor immune responses, suggesting a potential use of rIL-33 as a new immunotherapy option to treat established cancer.

In embryonal rhabdomyosarcoma (ERMS) and generally in sarcomas, the role of wild-type and loss or gain of function TP53 mutations remains largely undefined. Eliminating mutant or restoring wild-type p53 is challenging; nevertheless, understanding TP53 effects on tumorigenesis remains central to realizing better treatment outcomes. In ERMS, >70% of patients retain wild-type TP53, yet TP53 mutations when present in tumors are associated with poor prognosis. Employing a kRASG12D-driven ERMS tumor model and newly generated tp53 null (tp53-/-) zebrafish, we define both wild-type and patient-specific TP53 mutant effects on tumorigenesis. We demonstrate that tp53 is a major suppressor of tumor initiation, where tp53 loss expands tumors initiation from <35% to >97% of animals. Next, characterizing three patient-specific mutants finds that TP53C176F partially retains wild-type p53 apoptotic activity that can be exploited, while the TP53P153Δ and TP53Y220C mutants define two structural mutations that predispose to head musculature ERMS.

<p>Supplementary Figures and Tables</p>

<p>Supplementary Materials, Methods, and References</p>

<p>Supplementary Figures and Tables</p>