Targeting ALDHbright Human Carcinoma–Initiating Cells with ALDH1A1-Specific CD8+ T Cells

Abstract

Purpose Tumor cells expressing elevated aldehyde dehydrogenase (ALDH) activity attributed to ALDH1/3 isoforms have been identified as ALDHbright cells and have the properties attributed to cancer initiating cells (CIC). CIC represent the subpopulation of tumor cells that are resistant to conventional cancer treatments and highly tumorigenic in immunodeficient mice. They are considered to be responsible for tumor recurrence and metastasis. The ALDH1A1 isoform was previously identified as a tumor antigen recognized by CD8+ T cells. This study examines the ability of ALDH1A1-specific CD8+ T cells to eliminate ALDHbright cells and control tumor growth and metastases. Experimental Design ALDHbright cells were isolated by flow cytometry from HLA-A2+ human head and neck, breast and pancreas carcinoma cell lines using ALDEFLUOR® and tested for their tumorigenicity in immunodeficient mice. ALDH1A1-specific CD8+ T cells were generated in vitro and tested for their ability to eliminate CIC in vitro and in vivo by adoptive transfer to immunodeficient mice bearing human tumor xenografts. Results ALDHbright cells isolated by flow cytometry from HLA-A2+ breast, head and neck and pancreas carcinoma cell lines at low numbers (500 cells) were tumorigenic in immunodeficient mice. ALDHbright cells present in these cell lines, xenografts or surgically removed lesions were recognized by ALDH1A1-specific CD8+ T cells in vitro. Adoptive therapy with ALDH1A1-specific CD8+ T cells eliminated ALDHbright cells, inhibited tumor growth, metastases or prolonged survival of xenograft-bearing immunodeficient mice. Conclusions The results of this translational study strongly support the potential of ALDH1A1-based immunotherapy to selectively target CIC in human cancer.

Cancer stem cell vaccine inhibits metastases of primary tumors and induces humoral immune responses against cancer stem cells

“…ALDH (aldehyde dehydrogenase) activity, often measured via ALDEFLUOR assay, has been successfully used as a marker to enrich CSC populations 11,[17][18][19][20][21][22] in a variety of cancers including human melanoma 23 and head and neck squamous cell cancer. 18 We characterized CSC-enriched populations in 2 histologically distinct murine tumors (melanoma D5 and squamous cell cancer SCC7) and evaluated their immunogenicity by administering CSC-based vaccines in 2 genetically different syngeneic immunocompetent hosts followed by tumor challenge.…”

Whole cell melanoma vaccine genetically modified to stem cells like phenotype generates specific immune responses to ALDH1A1 and long-term survival in advanced melanoma patients

“…Using tumor-specific CD8 + T cells, they identified ALDH1A1 as a novel tumor antigen. Subsequently, Visus et al 20 showed that ALDH brigh tumor cells in human cancers were recognized by HLA-A2 restricted AHDL1A1 88-96 peptide specific CD8 + T cells and eliminated in vitro and in vivo . Moreover, in human tumor xenograft models they have demonstrated that adoptive transfer of ALDH1A1 specific CD8 + T cells inhibited the growth of subcutaneously implanted cells and induced lung metastases.…”

Targeting head and neck tumoral stem cells: From biological aspects to therapeutic perspectives

“…Studies on vaccination against antigen ALDH1A1+ of CSCs have been performed and have achieved significant progress. Visus et al [41] have demonstrated the ability in vivo of generated ALDH1A1 specific cytotoxic T lymphocytes to eliminate ALDH (bright) cells present in HLAA2+ HNSCC carcinoma cell lines. They also found antitumor activity by adoptive immunotherapy with ALDH1A1specific cytotoxic T lymphocytes in vivo.…”