The IFN-γ / IFN-γ Rα axis is involved in immunoediting of breast cancer that leads to the de novo generation of a novel breast cancer stem cell (BCSC)-like tumor variant and subsequent tumor recurrence (100.12)
Abstract Tumor dormancy remains a major hurdle in the treatment of cancers. Recently, the association between cancer stem cells (CSC) and tumor dormancy has been speculated in variety of cancers. Despite conventional therapies of breast cancer, most of the US deaths are attributed to relapse which is likely due to a failure of current treatment regimens to eliminate breast cancer stem cells (BCSC). We reported IFN-γ-induced HER-2/neu antigen loss and tumor relapse. We performed in vitro and in vivo studies using neu positive mammary carcinoma (MMC) tumors and their dominant negative (dn) IFN-γ Rα MMC sub-line. We showed that IFN-γ producing CD8+ T cells induced the de novo generation of a distinct BCSC variant that differed from conventional BCSC. The novel phenotype: i) is not intrinsically quiescent, ii) is reversible by blocking IFN-γ Rα signaling in the tumor, iii) upregulates serine protease inhibitors (SPI-6/PI-9) and MUC-1 that could render the tumors refractory to granzyme/perforin- and antibody-induced apoptosis, respectively, and iv) downregulates HER-2/neu expression upon emerging under the immune pressure. While HER-2/neu+ conventional BCSC have been shown to be sensitive to HER-2/neu-targeted immunotherapy, these novel BCSC-like phenotypes are refractory to such immunotherapy because of HER-2/neu loss. Identification of such tumor immunoediting pathways and mechanisms is expected to improve immunotherapy of breast cancer, by pathway blocking strategies.
Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)
1
Abstract The breast cancer stem cell (BCSC) hypotheses suggest that breast cancer is derived from a single tumor-initiating cell with stem-like properties, but the source of these cells is unclear. We previously observed that induction of an immune response against an epithelial breast cancer led in vivo to the T-cell–dependent outgrowth of a tumor, the cells of which had undergone epithelial to mesenchymal transition (EMT). The resulting mesenchymal tumor cells had a CD24−/loCD44+ phenotype, consistent with BCSCs. In the present study, we found that EMT was induced by CD8 T cells and the resulting tumors had characteristics of BCSCs, including potent tumorigenicity, ability to reestablish an epithelial tumor, and enhanced resistance to drugs and radiation. In contrast to the hierarchal cancer stem cell hypothesis, which suggests that breast cancer arises from the transformation of a resident tissue stem cell, our results show that EMT can produce the BCSC phenotype. These findings have several important implications related to disease progression and relapse. [Cancer Res 2009;69(7):2887–95]
Signatures Associated with Rejection or Recurrence in HER-2/
neu
–Positive Mammary Tumors
Abstract We have previously shown T-cell–mediated rejection of the neu-overexpressing mammary carcinoma cells (MMC) in wild-type FVB mice. However, following rejection of primary tumors, a fraction of animals experienced a recurrence of a neu antigen-negative variant (ANV) of MMC (tumor evasion model) after a long latency period. In the present study, we determined that T cells derived from wild-type FVB mice can specifically recognize MMC by secreting IFN-γ and can induce apoptosis of MMC in vitro. Neu transgenic (FVBN202) mice develop spontaneous tumors and cannot reject it (tumor tolerance model). To dissect the mechanisms associated with rejection or tolerance of MMC tumors, we compared transcriptional patterns within the tumor microenvironment of MMC undergoing rejection with those that resisted it either because of tumor evasion/antigen loss recurrence (ANV tumors) or because of intrinsic tolerance mechanisms displayed by the transgenic mice. Gene profiling confirmed that immune rejection is primarily mediated through activation of IFN-stimulated genes and T-cell effector mechanisms. The tumor evasion model showed combined activation of Th1 and Th2 with a deviation toward Th2 and humoral immune responses that failed to achieve rejection likely because of lack of target antigen. Interestingly, the tumor tolerance model instead displayed immune suppression pathways through activation of regulatory mechanisms that included in particular the overexpression of interleukin-10 (IL-10), IL-10 receptor, and suppressor of cytokine signaling (SOCS)-1 and SOCS-3. These data provide a road map for the identification of novel biomarkers of immune responsiveness in clinical trials. [Cancer Res 2008;68(7):2436–46]