Abstract

Two major barriers to cancer immunotherapy include tumor-induced immune suppression mediated by myeloid-derived suppressor cells and poor immunogenicity of the tumor-expressing self-antigens. To overcome these barriers, we reprogrammed tumor-immune cell cross-talk by combined use of decitabine and adoptive immunotherapy, containing tumor-sensitized T cells and CD25(+) NKT cells. Decitabine functioned to induce the expression of highly immunogenic cancer testis antigens in the tumor, while also reducing the frequency of myeloid-derived suppressor cells and the presence of CD25(+) NKT cells rendered T cells, resistant to remaining myeloid-derived suppressor cells. This combinatorial therapy significantly prolonged survival of animals bearing metastatic tumor cells. Adoptive immunotherapy also induced tumor immunoediting, resulting in tumor escape and associated disease-related mortality. To identify a tumor target that is incapable of escape from the immune response, we used dormant tumor cells. We used Adriamycin chemotherapy or radiation therapy, which simultaneously induce tumor cell death and tumor dormancy. Resultant dormant cells became refractory to additional doses of Adriamycin or radiation therapy, but they remained sensitive to tumor-reactive immune cells. Importantly, we discovered that dormant tumor cells contained indolent cells that expressed low levels of Ki67 and quiescent cells that were Ki67 negative. Whereas the former were prone to tumor immunoediting and escape, the latter did not demonstrate immunoediting. Our results suggest that immunotherapy could be highly effective against quiescent dormant tumor cells. The challenge is to develop combinatorial therapies that could establish a quiescent type of tumor dormancy, which would be the best target for immunotherapy.

Highlights

  • MDSCs are key cellular suppressors of anti-tumor immune responses in breast cancer patients

  • With the use of PBMCs of patients with early-stage breast cancer, we demonstrated previously that an optimal frequency of CD25+ NKT cells within reprogrammed immune cells, cultured in the presence of MDSCs/Mregs, induced them to lose/down-regulate CD11b, which was associated with HLA-DR up-regulation

  • This protection was associated with the presence of memory T cells, and CD25+ NKT cells that rendered T cells resistant to MDSC-mediated suppression [5]

Read more

Summary

Introduction

MDSCs are key cellular suppressors of anti-tumor immune responses in breast cancer patients. With the use of PBMCs of patients with early-stage breast cancer, we demonstrated previously that an optimal frequency of CD25+ NKT cells within reprogrammed immune cells, cultured in the presence of MDSCs/Mregs, induced them to lose/down-regulate CD11b, which was associated with HLA-DR up-regulation. Such phenotypic modulation was shown to promote anti-human epidermal growth factor receptor 2/neu immune responses in vitro [4]. Inclusion of CD25+ NKT cells in AIT should enhance the anti-tumor

Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call