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Cytotoxic lymphodepletion therapies augment antitumor immune responses. The generation and therapeutic efficacy of antitumor effector T cells (TEs) are enhanced during recovery from lymphopenia. Although the effects of lymphodepletion on naive T cells (TNs) and TEs have been studied extensively, the influence of lymphodepletion on suppressor cells remains poorly understood. In this study, we demonstrate a significant Increase of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in sublethally irradiated lymphopenic mice. These radioresistant Tregs inhibited the induction of TEs in tumordraining lymphnodes (TDLNs) during recovery from lymphopenia. The transfer of TNs into lymphopenic tumorbearing mice resulted in some antitumor effects; however, Treg depletion after wholebody irradiation and reconstitution strongly inhibited tumor progression. Further analyses revealed that tumorspecific T cells were primed from the transferred TNs, whereas the Tregs originated from irradiated recipient cells. As in irradiated lymphopenic mice, a high percentage of Tregs was observed in cyclophosphamidetreated lymphopenic mice. The inhibition of Tregs in cyclophosphamidetreated mice significantly reduced tumor growth. These results indicate that the Tregs that survive cytotoxic therapies suppress antitumor immunity during recovery from lymphopenia and suggest that approaches to deplete radio and chemoresistant Tregs can enhance cancer immunotherapies. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that most solid malignancies consist of heterogeneous tumor cells and that a relatively small subpopulation, which shares biological features with stem cells, survives through potentially lethal stresses such as chemotherapy and radiation treatment. Since the survival of this subpopulation of cancer stem cells (CSC) plays a critical role in recurrence, it must be eradicated in order to cure cancer. We previously reported that vaccination with CD133 murine melanoma cells exhibiting biological CSC features induced CSC-specific effector T cells. These were capable of eradicating CD133 tumor cells in vivo, thereby curing the parental tumor. In the current study, we indicated that DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 3, X-linked (DDX3X) is an immunogenic protein preferentially expressed in CD133 tumor cells. Vaccination with DDX3X primed specific T cells, resulting in protective and therapeutic antitumor immunity. The DDX3X-primed CD4 T cells produced CD133 tumor-specific IFNγ and IL-17 and mediated potent antitumor therapeutic efficacy. DDX3X is expressed in various human cancer cells, including lung, colon, and breast cancer cells. These results suggest that anti-DDX3X immunotherapy is a promising treatment option in efforts to eradicate CSC in the clinical setting. [ABSTRACT FROM AUTHOR]