Abstract
BackgroundTumor tolerance and immune suppression remain formidable obstacles to the efficacy of immunotherapies that harness the immune system to eradicate breast cancer. A novel syngeneic mouse model of breast cancer metastasis was developed in our lab to investigate mechanisms of immune regulation of breast cancer. Comparative analysis of low-metastatic vs. highly metastatic tumor cells isolated from these mice revealed several important genetic alterations related to immune control of cancer, including a significant downregulation of cd1d1 in the highly metastatic tumor cells. The cd1d1 gene in mice encodes the MHC class I-like molecule CD1d, which presents glycolipid antigens to a specialized subset of T cells known as natural killer T (NKT) cells. We hypothesize that breast cancer cells, through downregulation of CD1d and subsequent evasion of NKT-mediated antitumor immunity, gain increased potential for metastatic tumor progression.Methodology/Principal FindingsIn this study, we demonstrate in a mouse model of breast cancer metastasis that tumor downregulation of CD1d inhibits iNKT-mediated antitumor immunity and promotes metastatic breast cancer progression in a CD1d-dependent manner in vitro and in vivo. Using NKT-deficient transgenic mouse models, we demonstrate important differences between type I and type II NKT cells in their ability to regulate antitumor immunity of CD1d-expressing breast tumors.Conclusions/SignificanceThe results of this study emphasize the importance of determining the CD1d expression status of the tumor when tailoring NKT-based immunotherapies for the prevention and treatment of metastatic breast cancer.
Highlights
Significant progress has been made over the past few decades in developing breast cancer immunotherapies that inhibit tumor progression and prevent metastasis [1]
Several tumor types have been shown to express CD1d, and tumor expression of CD1d has been directly correlated with the ability of invariant NKT (iNKT) cells to induce direct tumor cytolysis in vitro and promote iNKT-mediated tumor immunity in vivo [25,51]
This is the first study to address the role of CD1d expression and natural killer T (NKT)-mediated antitumor immunity in regulating breast cancer metastasis
Summary
Significant progress has been made over the past few decades in developing breast cancer immunotherapies that inhibit tumor progression and prevent metastasis [1]. While recent advances in tumor vaccines and T cell-based immunotherapies appear promising, tumor tolerance and immune suppression remain formidable obstacles to eradicating breast cancer [2]. It is widely believed in the field of metastasis that tumor cells must acquire multiple genetic alterations to enable colonization in distant organ sites [3]. Cancer cells have been documented to downregulate or alter MHC class I molecules and their presentation of tumor antigens to escape immune surveillance, a process known as immunoediting [6,7]. Identifying critical genetic alterations that enable immune evasion and tumor tolerance will facilitate the development of immunotherapies that eliminate breast cancer. We hypothesize that breast cancer cells, through downregulation of CD1d and subsequent evasion of NKT-mediated antitumor immunity, gain increased potential for metastatic tumor progression
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