Antitumor Immunity and Cancer Stem Cells

Abstract

Self-renewing cancer stem cells (CSC) capable of spawning more differentiated tumor cell progeny are required for tumorigenesis and neoplastic progression of leukemias and several solid cancers. The mechanisms by which CSC cause tumor initiation and growth are currently unknown. Recent findings that suggest a negative correlation between degrees of host immunocompetence and rates of cancer development raise the possibility that only a restricted minority of malignant cells, namely CSC, may possess the phenotypic and functional characteristics to evade host antitumor immunity. In human malignant melanoma, a highly immunogenic cancer, we recently identified malignant melanoma initiating cells (MMIC), a novel type of CSC, based on selective expression of the chemoresistance mediator ABCB5. Here we present evidence of a relative immune privilege of ABCB5+ MMIC, suggesting refractoriness to current immunotherapeutic treatment strategies. We discuss our findings in the context of established immunomodulatory functions of physiologic stem cells and in relation to mechanisms responsible for the downregulation of immune responses against tumors. We propose that the MMIC subset might be responsible for melanoma immune evasion and that immunomodulation might represent one mechanism by which CSC advance tumorigenic growth and resistance to immunotherapy. Accordingly, the possibility of an MMIC-driven tumor escape from immune-mediated rejection has important implications for current melanoma immunotherapy.

Cancer-Initiating Cells from Colorectal Cancer Patients Escape from T Cell–Mediated Immunosurveillance In Vitro through Membrane-Bound IL-4

“…In fact, proliferation of T cells was inhibited by coculture with autologous or allogeneic CICs, but not with FBS tumor cells. CIC-associated factors, such as TGF-b, IL-10, IL-13, galectin, and PDGE2, which can play a negative regulatory role in the induction of tumor reactive T cells, have been described (12)(13)(14) and, notably, shown to be shared with normal stem cells as well (30). The complexity of this issue is demonstrated by the evidence that none of the molecules described above have been found to be specifically expressed or upregulated in CICs that we have isolated in vitro (data not shown), in line with the results that have been previously published by our group for GBM (10).…”

“…Cancer-testis Ags have been found to be expressed by mesenchymal stem cells and to regulate the epithelial-to-mesenchymal transition, a process involved in development of metastases; thus these Ags may possibly have a role in the stemness properties of cancer cells and could represent target molecules for immunotherapy (11). Nevertheless, antitumor immunity could be attenuated by tumor-related immunosuppressive mechanisms that have been described in association with CICs isolated from melanoma or GBM (12)(13)(14). These findings suggest that a detailed immunological characterization of CICs isolated from different human tumors is a relevant issue to design new CICtargeted immunotherapeutic interventions.…”

Granulin–Epithelin Precursor Renders Hepatocellular Carcinoma Cells Resistant to Natural Killer Cytotoxicity

“…Recently, ABCB5 þ malignant melanoma-initiating cells were found to modulate antitumor immunity by preferentially inhibiting IL2-dependent T-cell activation and promoting induction of regulatory T cells (14,16). Moreover, CD200 þ CSCs were found to suppress antitumor immunity by downregulating the expression of Th1 cytokines and costimulatory molecules, in ovarian cancer, melanoma, and leukemia (17,18).…”

“…It has been suggested that immunoevasion is restricted to CSCs, enabling them to survive in the host (13)(14)(15). Recently, ABCB5 þ malignant melanoma-initiating cells were found to modulate antitumor immunity by preferentially inhibiting IL2-dependent T-cell activation and promoting induction of regulatory T cells (14,16).…”

Cancer stem cell hypothesis: a brief summary and two proposals

“…For example, a novel type of CSCs, ABCB5 ? malignant melanoma initiating cells (MMIC) were reported refractory to current immunotherapeutic treatment strategies (Schatton and Frank 2009). And interestingly, CSCs derived from glioblastoma multiform patients could suppress immune responses by impeding T-cell proliferation and activation, inducing T-cell apoptosis and inhibiting the phagocytosis ability of MUs/microglia (Wei et al 2010a, b;Wu et al 2010).…”