Targeting cancer stem-like cells: A novel combination strategy for effectively targeting cancer stem-like cells

    loading  Checking for direct PDF access through Ovid

Excerpt

Immunotherapy is now established as the fourth pillar of cancer therapy alongside surgery, radiation and chemotherapy. The major success of cancer immunotherapy to date has been the use of therapies targeting immune checkpoints such as PD-1 and CTLA-4, which act to enhance the ability of tumor-antigen specific CD8+ T cells to target cancer cells.1 Similarly, adoptive cellular therapy of expanded tumor-infiltrating lymphocytes or vaccines based on recognition of tumor (neo)antigens are also promising approaches, which make use of the cytotoxic activity of CD8+ T cells. Although these strategies have shown considerable promise in some patients, the effectiveness of anti-tumor CD8+ T cells is limited by several factors, including local tumor-induced immunosuppression and the requirement of tumors to express MHC-I, which is often downregulated as a tumor escape mechanism.2 Furthermore, the cancer stem cell (CSC) population, reported to be important for tumor progression and metastasis, is known to be resistant to anti-tumor T cells (Figure 1). Therefore, there is a pressing need to develop strategies to further enhance the activity of CD8+ T cells in patients who would otherwise be non-responsive to immunotherapy.
The recent publication by Chen et al.3 highlights the potential for utilizing γδ T cells to enhance the sensitivity of CSCs to CD8+ T-cell mediated killing. First, Chen et al.3 developed a unique model to isolate CSCs from ras/SV40 large T-antigen transformed cells and compared their phenotype to the non-CSC population. The CSCs were identified as mesenchymal-like cells through their lack of expression of epithelial markers cytokeratin-14/18 and their positive staining for vimentin. Moreover, the stem cell properties of the identified CSCs were also shown by their renewal properties in spheroid cultures and their ability to form tumors in NOD scid gamma mice, which was significantly enhanced above and beyond the non-CSC population.
Using an intricate co-culture system in which FluM1/ CMV-specific CD8+ T cells were co-cultured with cancer cells that were either retrovirally engineered to express the endogenous FluM1 or pulsed with peptides to the immunodominant epitopes of FluM1/ CMV, the authors show that the CD8+ T cells were significantly less able to lyse the CSC population. Since the CSCs express less MHC-I and ICAM-1 (CD54) than their non-CSC counterparts, Chen et al.3 postulated that the restoration of MHC-I and ICAM-1 expression on CSCs could enhance their susceptibility to T-cell mediated killing. One potential way to achieve this therapeutically is induction of an innate immune response which can consequently enhance tumor immunogenicity to CD8+ T cells via a number of mechanisms, including the production of IFN-γ which is known to regulate MHC-I.4 The use of γδ T cells has previously been postulated in cancer immunotherapy due to their high cytotoxic potential and their ability to target tumors in a non-MHC-restricted fashion.5 One method to enhance human Vγ9Vδ2 T cell activity is through the use of aminobisphosphonates such as zoledronate,5 which interfere with phosphoantigen-processing enzymes and consequently enhance the presentation of phosphoantigens recognized by Vγ9Vδ2 T cells. In the current study, the use of zoledronate was shown to enable γδ-mediated killing of both non-CSC and CSC populations and to synergistically enhance the killing activity of CD8+ T cells through the IFN-γ-driven upregulation of MHC-I and ICAM-1 (Figure 1).
The findings in this study demonstrating effective targeting of CSCs could have major implications for the effective treatment of metastatic disease, given the current problem of the resistance of this population to standard therapies such as chemotherapy, often leading to cancer relapse in patients.
Another important escape mechanism used by cancer cells following conventional treatments is the downregulation of MHC-I rendering them ignorant to CD8+ T-cell recognition.
    loading  Loading Related Articles