Vaccination with Mage-b DNA induces CD8 T-cell responses at young but not old age in mice with metastatic breast cancer

Abstract

BACKGROUND: Elderly individuals react less efficiently to vaccines than do adults, mainly because of T-cell unresponsiveness. In this study, we analysed whether tumour-associated antigen (TAA)-specific CD8 T-cell responses could be induced by vaccination in old mice with metastatic breast cancer. METHODS: The effect of pcDNA-3.1-and Listeria-based vaccines, expressing TAA Mage-b, on Mage-b-specific immune responses was tested in spleens and draining lymph nodes (LNs) of mild (4TO7cg) and aggressive (4T1) syngeneic metastatic mouse breast tumour models at young (3 months) and old (20 months) age. RESULTS: Interferon g and interleukin-2 levels increased significantly in draining LNs and spleens of Mage-b-vaccinated mice compared with those in control groups at young but not old age in both mouse tumour models. A significant increase was observed in the number of IFNg-producing Mage-b-specific CD8 T cells after Mage-b vaccination in the 4T1 model at young but not old age. This correlated with a reduced protective effect of Mage-b vaccination against metastatic breast cancer at old compared with young age. CONCLUSIONS: The absence of CD8 T-cell responses after Mage-b vaccination and the accompanying reduced protection against metastatic breast cancer in old compared with young mice point towards the need for tailoring cancer vaccination to older age.

Cancer Vaccination at Older Age

“…Vaccination of both models with Mage-b was highly effective against metastases at young but not at old age, and this correlated with strong Mage-b-specific T cell responses in vitro and in vivo at young but not at old age [3]. Interestingly, we found that Mage-b vaccination activated macrophages and NK cells (producing IFNγ) in old mice [3].…”

“…Vaccination of both models with Mage-b was highly effective against metastases at young but not at old age, and this correlated with strong Mage-b-specific T cell responses in vitro and in vivo at young but not at old age [3]. Interestingly, we found that Mage-b vaccination activated macrophages and NK cells (producing IFNγ) in old mice [3]. In another more recent vaccine study with Mage-b delivered through a highly attenuated L. monocytogenes, we found a dramatic effect on the metastases in the 4T1 model at young age [40].…”

“…For instance, a clinical trial is ongoing with bortezomib which sensitizes tumor cells for TRAIL-and FasL-mediated destruction by NK cells in cancer patients between 20 and 70 years (NCT00720785) [29]. We found NK cell responses (producing IFNγ) in vivo in old mice with metastatic breast cancer after vaccination with pcDNA3.1-Mage-b [3], or with Listeria-Mage-b [unpubl. results].…”

“…In our laboratory, we developed a DNA vaccine of Mage-b (pcDNA3.1-Mage-b) and tested this vaccine at young and old age in two syngeneic metastatic mouse breast tumor models, 4TO7cg and 4T1, both overexpressing Mage-b in metastases and primary tumors [3]. Vaccination of both models with Mage-b was highly effective against metastases at young but not at old age, and this correlated with strong Mage-b-specific T cell responses in vitro and in vivo at young but not at old age [3].…”

“…Immunotherapy may be our best and most benign option for preventing or curing metastatic cancer in such patients. Unfortunately, cancer immunotherapy is less effective at old than at young age, due to T cell unresponsiveness, especially in the tumor microenvironment (TME) [3,4]. Various age-related changes of the immune system, such as lack of naïve T cells, defects in activation pathways of T cells and antigen-presenting cells (APC), and immune suppression in the TME contribute to T cell unresponsiveness at older age [4].…”