Autologous CTL response against cancer stem‐like cells/cancer‐initiating cells of bone malignant fibrous histiocytoma

Abstract

Malignant fibrous histiocytoma (MFH) of the bone is an aggressive tumor with high rates of local recurrence and metastasis. The development of novel therapeutic approaches is critical to improve the prognosis of patients with MFH. We reported previously that the side population (SP) cells of the MFH2003 bone MFH cell line have the characteristics of cancer stem-like cells (CSC)/cancer-initiating cells. In the present study, to establish immunotherapy targeting CSC, we analyzed cell surface immune molecules on SP cells of the MHF2003 cell line, as well as autologous CTL responses against these SP cells in the tumor microenvironment and peripheral circulating lymphocytes, using autologous tumor-infiltrating lymphocytes and autologous CTL clones derived from peripheral blood, respectively. We found that the SP cells expressed human leukocyte antigen (HLA) Class I molecules on the cell surface. The autologous tumor-infiltrating lymphocyte line TIL2003 recognized both the SP and main population cells of the MFH2003 cell line. Next, we induced the CTL clone Tc4C-6 by mixed lymphocyte tumor cell culture using autologous peripheral blood mononuclear cells and freshly isolated SP cells, followed by a limiting dilution procedure. The Tc4C-6 clone showed specific cytotoxicity against the SP cells. Moreover, the cytotoxicity against SP cells was blocked by the anti-HLA Class I antibody W6/32. In conclusion, the findings of the present study support the idea that CSC of bone MFH are recognized by autologous CTL in the tumor microenvironment and peripheral circulating lymphocytes. Thus, CTL-based immunotherapy could target CSC of bone sarcoma to help prevent tumor recurrence.

Olfactory Receptor Family 7 Subfamily C Member 1 Is a Novel Marker of Colon Cancer–Initiating Cells and Is a Potent Target of Immunotherapy

“…To address the feasibility of CIC-targeting immunotherapy, we isolated CRC CICs as side population (SP) cells by Hoechst 33342 staining and found that SP cells are susceptible to CTLs as are non-CIC main population (MP) cells (14). We also reported that CICs of malignant fibrous histiocytoma could be recognized by autologous CTLs derived from tumor-infiltrating lymphocytes (15). Thus, CTLs can recognize treatment-resistant CICs.…”

Overcoming Therapeutic Resistance of Bone Sarcomas: Overview of the Molecular Mechanisms and Therapeutic Targets for Bone Sarcoma Stem Cells

“…Indeed, this oncolytic virus was previously confirmed to be effective by targeting gastric CSCs [104]. Kano et al found that the SP cells showed the expression of human leukocyte antigen (HLA) class I molecules on the cell surface, and the CTL clone Tc4C-6, induced by mixed lymphocyte tumor cell culture using autologous peripheral blood mononuclear cells and freshly isolated SP cells, showed specific cytotoxicity against the SP cells [105]. These compounds could be candidates to overcome bone sarcoma stem cells but have not yet been tested preclinically for bone sarcomas.…”

Immunotherapy: Newer Therapeutic Armamentarium against Cancer Stem Cells

“…Subsequently, noteworthy anticancer effects, ensuing in retarded tumor growth and increased survival, were revealed by these ALDH high -CD8 + T cells [106]. Moreover, HLA-I molecules and autologous cytotoxic T lymphocytes (CTLs) were expressed by CSCs that were purified as SP from bone malignant fibrous histiocytoma (MFH) in vitro coculture with SP cells [107]. Also, an important indication that the CTL clone specifically recognizes MFH CSC-specific antigens came from the observation that CTL clones are biased towards the recognition of SP cells rather than non-SP cells [107].…”