Received date: April 20, 2013; Accepted date: June 04, 2013; Published date: June 06, 2013
Citation: Ogawa T, Hirohashi Y, Torigoe T, Sato N, Hirata K (2013) Immunotherapy Targeting Cancer Stem Cells of Human Colorectal Cancer. J Gastroint Dig Syst S12:014. doi:10.4172/2161-069X.S12-014
Copyright: © 2013 Ogawa T, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Colorectal cancer is one of the most common malignancies worldwide. Despite improvements in surgical therapy and chemotherapy, the overall survival rate of patients with recurrence or metastatic cancer has not improved significantly in the past several decades. Treatment resistance makes the disease incontrollable, and recent basic research has revealed that cancer stem-like cells (CSCs) or cancer-initiating cells (CICs) are involved in treatment resistance. Therefore, eradicating CSCs/CICs is a key approach to improve colorectal cancer treatment. Cancer immunotherapy is expected to become the fourth cancer treatment option, and several studies have shown that CSCs/CICs can be targeted by immunotherapy. In this review article, we summarize the potency of immunotherapy as CSC/CIC-targeting therapy and the future perspectives of CSC/CIC-targeting immunotherapy.
Colon cancer; Cancer stem cell; Immunotherapy
CSC: Cancer Stem-like Cell; CIC: Cancer-Initiating Cell; TAA: Tumor-Associated Antigen; CTL: Cytotoxic T Lymphocyte; NK: Natural Killer
Colorectal cancer is one of the most common malignancies worldwide. In Japan, the morbidity and mortality of colorectal cancer has been increasing year by year, and cancer deaths due to colorectal cancer are ranked third in men and first in women. Due to improvements in diagnostic and therapeutic technology, the 5-year survival rate of early-stage colorectal cancers has reached almost 100%; however, the 5-year survival rate of patients with advanced colorectal cancer, especially patients with distant metastasis or recurrence, is still less than 20%. Chemotherapies for advanced colorectal cancer have been performed mainly with a combination of 5-fluorouracil (5-FU), leucovorin (LV) and oxaliplatin (L-OHP), and molecular targeting therapy with monoclonal antibodies for VEGF (bevacizumab) EGFR (cetuximab) has recently become available in clinical settings. Progress in chemotherapy for colorectal cancer has been remarkable; however, overall survival has not improved to a satisfactory level.
Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are defined as a small population of cancer cells that have (i) high tumorinitiating ability, (ii) self renewal ability, and (iii) differentiation ability . Recent studies have revealed that CSCs/CICs are resistant to standard cancer therapies, and CSCs/CICs have thus been suggested to have roles in cancer recurrence after treatment and in distant metastasis [2,3]. Therefore, eradication of CSCs/CICs is essential to improve clinical outcomes.
CSCs/CICs were first isolated in leukemia as leukemia stem cells [4,5]. In subsequent works, CSCs/CICs were successfully isolated in several solid malignancies. Colorectal CSCs/CICs were isolated using cell surface markers including CD133 by the ALDEFLUOR assay and as side population (SP) cells [6-9]. Colorectal CSCs/CICs exhibited greater tumor-initiating ability than that of the non-CSC/CIC population. Furthermore, colorectal CSCs/CICs showed resistance to chemotherapeutic reagents as was found for CSCs/CICs derived from other types of malignancies.
Since colorectal CSCs/CICs are resistant to standard cancer therapies, they should be eradicated to cure the disease. Thus, CSC/ CIC research has been focused on how to treat colorectal CSCs/CICs. Cancer immunotherapy might be a good candidate. The immune system is consists of antigen-specific acquired immunity and antigennon- specific innate immunity. Several effectors have been shown to successfully recognize treatment-resistant colorectal CSCs/CICs, including cytotoxic T lymphocytes (CTLs) for acquired cellular immunity, antibodies for acquired humoral immunity, natural killer (NK) cells and γδT cells for innate immunity .
Cytotoxic T lymphocytes (CTLs)
CTLs are effector cells that are related to cellular immunity. CTLs recognize antigenic peptides presented by major histocompatibility antigen (MHC) class I molecule. Unlike NK cells and γδT cells, CTLs recognize target cells in an antigen-specific manner. Therefore, it is essential to express both MHC class I and antigens to be recognized by CTLs. In our previous study, CSCs/CICs derived as SP cells were shown to express MHC class I molecule at a level similar to that in non-CSCs/CICs isolated as main population cells . Furthermore, colorectal CSCs/CICs express a TAA, CEP55. We compared the susceptibility to CEP55-specific CTLs of CSCs/CICs and that of non- CSCs/CICs and found that both colorectal CSCs/CICs and non-CSCs/ CICs can be recognized by CEP55-specific CTLs at similar level . Therefore, treatment resistant colorectal CSCs/CICs can be recognized by CTLs. In the following works, we found that colorectal CSCs/CICs express several TAAs including DNAJB8 and cancer/testis antigens [11,12]. These antigens are candidates for colorectal CSC/CIC-targeting immunotherapy.
Natural killer (NK) cells
NK cells are effector cells of innate immunity and they recognize target cells by ligands of natural cytotoxicity receptors and are not specific for antigens. A recent study has revealed that colorectal CSCs/CICs isolated as sphere-forming cells express high levels of ligands of natural cytotoxicity receptors and that NK cells efficiently recognize colorectal CSCs/CICs .
γδT cells are T cell subpopulation that have distinct T cell receptors (TCR) consisting of a γ–chain and δ–chain, different from αβT cells, which have TCR composed of an α-chain and β-chain. The proportion of γδT cells in total T cells in epithelial lymphocytes is only 3% to 5% but, interestingly, γδT cells account for about 50% of cells in intestinal mucosa. Todaro et al. reported that zoledronate-activated Vγ9Vδ2 T cells efficiently recognize colorectal CSCs/CICs . CTLs, NK cells and γδT cells kill target cells by secretion of cytotoxic granules that include perforin and granzymes. Therefore, these findings indicate that treatment-resistant colorectal CSCs/CICs are sensitive to apoptotic cell death induced by perforin and granzymes.
Antibodies are effector molecules of the humoral immune system, and several oncoprotein-specific monoclonal antibodies have been approved and are in clinical use for malignant diseases. Colorectal CSC/CIC-specific cell surface proteins can be targets of antibodies. Dallas et al. described that chemotherapy resistant colorectal CSCs/ CICs induced by 5-fluorouracil (5FU) and oxaliplatin express a high level of insulin-like growth factor 1 receptor (IGF1R). Treatment with anti-IGF1R monoclonal antibody was shown to suppress the growth of colorectal CSCs/CICs both in virto and in vivo . A similar approach using anti-DLL4 monoclonal antibody has been reported . Therefore, colorectal CSC/CIC-specific monoclonal antibodies can be candidates for colorectal CSC/CIC-targeting immunotherapy.
As described above, CTLs, NK cells, γδT cells and antibodies efficiently recognize and target colorectal CSCs/CICs. NK cells and γδT cells are non-specific effectors, and these effectors should recognize both colorectal CSCs/CICs and non-CSCs/CICs. Therefore, NK cells and γδT cells might be good candidates to treat evident tumor, since a tumor is composed of a large proportion of non-CSCs/CICs and a small proportion of CSCs/CICs. CTLs and antibodies are antigen-specific effectors, and they are candidate for specific eradication of CSCs/CICs. After induction of CTLs in vivo, some antigen-specific CD8 + T cells remain for a long time as memory T cells, and CTLs might thus be a good candidate for long-lasting immunization such as immunization for prevention of relapse. Antibodies are not affected by the immune status of the patient, and antibodies might thus be candidates for treatment of immune-suppressed patients.
Colorectal CSCs/CICs are resistant to standard cancer therapies, whereas they can be targeted by immunological effectors. Therefore, cancer immunotherapy combined with other standard cancer therapies is an attractive approach. Several cancer immunotherapies have already been approved and several clinical trials are ongoing. Therefore, it is expected that colorectal CSC/CIC-targeting immunotherapy and a protocol of combined standard cancer therapy and colorectal CSC/ CIC-targeting immunotherapy will be established in the near future.
The authors have no financial conflict of interest.
This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (grant Nos. 16209013, 17016061 and 15659097), for Practical Application Research from the Japan Science and Technology Agency, and for Cancer Research (15-17 and 19-14) from the Ministry of Health, Labor and Welfare of Japan, Ono Cancer Research Fund (to N. S.) and Takeda Science Foundation (to Y. H.). This work was supported in part by the National Cancer Center Research and Development Fund (23-A-44).
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