In MLH1-/- mice representative of mismatch repair deficiency (MMR-D)-associated syndromes, Maletzki et al. tested the prophylactic and therapeutic use of an allograft tumor cellular lysate vaccine. Prophylactic vaccination increased tumor-reactive circulating T cells and delayed tumor growth, while therapeutic vaccination reduced tumor burden and prolonged overall survival. Vaccination increased CD4+ and CD8+ T cell infiltration, cytotoxic T cells, and NK cells in tumors, which demonstrated upregulation of PD-L1 and increased mutation burden.

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 IFNgamma 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.

Author Info: (1) Molecular Oncology and Immunotherapy, Department of General Surgery, Rostock University Medical Center, Rostock, Germany. (2) Institute for Biostatistics and Informatics in Medicine and Ageing

Author Info: (1) Molecular Oncology and Immunotherapy, Department of General Surgery, Rostock University Medical Center, Rostock, Germany. (2) Institute for Biostatistics and Informatics in Medicine and Ageing Research - IBIMA Rostock University Medical Center, Rostock, Germany. (3) Institute for Biostatistics and Informatics in Medicine and Ageing Research - IBIMA Rostock University Medical Center, Rostock, Germany. (4) Institute for Biostatistics and Informatics in Medicine and Ageing Research - IBIMA Rostock University Medical Center, Rostock, Germany. (5) Molecular Oncology and Immunotherapy, Department of General Surgery, Rostock University Medical Center, Rostock, Germany. (6) Core Facility Multimodal Small Animal Imaging, Rostock University Medical Center, Rostock, Germany. (7) Molecular Oncology and Immunotherapy, Department of General Surgery, Rostock University Medical Center, Rostock, Germany.

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