Cellular vaccination of MLH1−/− mice – an immunotherapeutic proof of concept study

OncoImmunology

Jan Stenzel¹  Georg Fuellen²  Mohamed Hamed²  Yvonne Saara Gladbach²  Marie-Luise Semmler³  Claudia Maletzki³  Michael Linnebacher³ 

[1] Core Facility Multimodal Small Animal Imaging, Rostock University Medical Center;Institute for Biostatistics and Informatics in Medicine and Ageing Research – IBIMA Rostock University Medical Center;Rostock University Medical Center;

关键词: cellular vaccine;    mmr deficiency;    in vivo imaging;    tumor microenvironment;    target gene identification;   

DOI  :  10.1080/2162402X.2017.1408748

来源: DOAJ

【 摘 要 】

Mismatch-repair deficiency (MMR-D) is closely linked to hypermutation and accordingly, high immunogenicity. MMR-D-related tumors thus constitute ideal vaccination targets for both therapeutic and prophylactic approaches. Herein, the prophylactic and therapeutic impact of a cellular vaccine on tumor growth and tumor-immune microenvironment was studied in a murine MLH1−/− knockout mouse model. Prophylactic application of the lysate (+/− CpG ODN 1826) delayed tumor development, accompanied by increased levels of circulating T cell numbers. Therapeutic application of the vaccine prolonged overall survival (median time: 11.5 (lysate) and 12 weeks (lysate + CpG ODN) vs. 3 weeks (control group), respectively) along with reduced tumor burden, as confirmed by PET/CT imaging and immune stimulation (increased CD3+CD8+ T – and NK cell numbers, reduced levels of TIM-3+ cells in both treatment groups). Coding microsatellite analysis of MMR-D-related target genes revealed increased mutational load upon vaccination (total mutation frequency within 28 genes: 28.6% vaccine groups vs. 14.9% control group, respectively). Reactive immune cells recognized autologous tumor cells, but also NK cells target YAC-1 in IFNγ ELISpot and, even more importantly, in functional kill assays. Assessment of tumor microenvironment revealed infiltration of CD8+ T-cells and granulocytes, but also upregulation of immune checkpoint molecules (LAG-3, PD-L1). The present study is the first reporting in vivo results on a therapeutic cellular MMR-D vaccine. Vaccination-induced prolonged survival was achieved in a clinically-relevant mouse model for MMR-D-related diseases by long-term impairment of tumor growth and this could be attributed to re-activated immune responses.

【 授权许可】

Unknown