Protective Cancer Vaccine Using Genetically Modified Hematopoietic Stem Cells.

Xiaofang Xiong,Jin-Ming Yang,Jugal Das,Jianxun Song,Xingcong Ren,Jianyong Song,Bing Ni

doi:10.3390/vaccines6030040

Abstract

Hematopoietic stem cells (HSCs) yield both the myeloid and lymphoid lineages of blood cells and can be reprogrammed into tumor antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) to prevent tumor growth. However, the optimal approach for differentiating tumor Ag-specific CTLs from HSCs, such as HSC-CTLs, remains elusive. In the current study, we showed that a combination of genetic modification of HSCs and in vivo T cell development facilitates the generation of Ag-specific CTLs that suppressed tumor growth. Murine HSCs, which were genetically modified with chicken ovalbumin (OVA)-specific T cell receptor, were adoptively transferred into recipient mice. In the following week, mice were administered with intraperitoneal injections of an agonist α-Notch 2 antibody and cytokines (rFlt3L and rIL-7) three times. After another two weeks, mice received a subcutaneous inoculation of B16-OVA melanoma cells that express OVA as a surrogate tumor Ag, before the anti-tumor activity of HSC-derived T cells was assessed. OVA-specific CTLs developed in vivo and greatly responded to OVA Ag stimulation ex vivo. In addition, mice receiving genetically modified HSCs and in vivo priming established anti-tumor immunity, resulting in the suppression of tumor growth. These results reported in this present study provide an alternative strategy to develop protective cancer vaccines by using genetically modified HSCs.

Highlights

In the last few years, the growing advancements in cellular immunology and tumor–host immune interactions has led to promising development of various immunotherapeutic approaches, including the blockade of immune checkpoints, induction of cytotoxic T lymphocytes (CTLs), adoptive cell transfer (ACT)-based therapy and modulation of tumor microenvironment (TME) to facilitate CTL activity
Our strategy to generate naive tumor Ag-specific Hematopoietic stem cells (HSCs)-CTLs may be applied for the development of protective cancer vaccines
Cells infiltrating into melanoma tissues in mice receiving T cell receptor (TCR) gene-transduced HSCs and in vivo development, which was similar to the mice receiving CD8+ T cells from OT-I TCR transgenic mice by flow cytometry (Figure 4A) and immunohistological staining (Figure 4B). These findings indicate that the ACT of TCR gene-transduced HSCs and in vivo development can develop tumor Ag-specific CTL

Summary

Introduction

In the last few years, the growing advancements in cellular immunology and tumor–host immune interactions has led to promising development of various immunotherapeutic approaches, including the blockade of immune checkpoints, induction of cytotoxic T lymphocytes (CTLs), adoptive cell transfer (ACT)-based therapy and modulation of tumor microenvironment (TME) to facilitate CTL activity. T lymphocytes (TILs) that were activated and expanded ex vivo has shown positive clinical outcomes in patients with metastatic malignancy [1]. In spite of the impressive progress in the field of T cell-based therapy, the clinical outcome remains limited or less satisfactory due to a variety of factors that lessen anti-tumor immunity, which include limited in vivo T cell expansion and persistence, tumor escape mechanisms, target antigen (Ag) selection, TME, Vaccines 2018, 6, 40; doi:10.3390/vaccines6030040 www.mdpi.com/journal/vaccines. Successful strategies to solve these problems should drastically progress cancer immunotherapy and are urgently desired

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Results

Conclusion