In vivo vaccination with cell line-derived whole tumor lysates: neoantigen quality, not quantity matters
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Journal of Translational Medicine Open Access
RESEARCH
In vivo vaccination with cell line‑derived whole tumor lysates: neoantigen quality, not quantity matters Inken Salewski1†, Yvonne Saara Gladbach2,3,4†, Steffen Kuntoff1, Nina Irmscher1, Olga Hahn5, Christian Junghanss1 and Claudia Maletzki1*
Abstract Background: Cancer vaccines provide a complex source of neoantigens. Still, increasing evidence reveals that the neoantigen quality rather than the quantity is predictive for treatment outcome. Methods: Using the preclinical Mlh1−/− tumor model, we performed a side-by side comparison of two autologous cell-line derived tumor lysates (namely 328 and A7450 T1 M1) harboring different tumor mutational burden (TMB; i.e. ultra-high: 328; moderate-high: A7450 T1 M1). Mice received repetitive prophylactic or therapeutic applications of the vaccine. Tumor incidence, immune responses and tumor microenvironment was examined. Results: Both tumor cell lysates delayed tumor formation in the prophylactic setting, with the A7450 T1 M1 lysate being more effective in decelerating tumor growth than the 328 lysate (median overall survival: 37 vs. 25 weeks). Comparable results were achieved in therapeutic setting and could be traced back to antigen-driven immune stimulation. Reactive T cells isolated from A7450 T1 M1-treated mice recognized autologous M lh1−/− tumor cells in IFNγ ELISpot, but likewise YAC-1 cells, indicative for stimulation of both arms of the immune system. By deciphering local effects, vaccines shaped the tumor microenvironment differently. While A7450 T1 M1 prophylactically vaccinated tumors harbored low numbers of myeloid-derived suppressor cells (MDSC) and elevated CD8-T cell infiltrates, vaccination with the 328 lysate evoked MDSC infiltration. Similar effects were seen in the therapeutic setting with stable disease induction only upon A7450 T1 M1 vaccination. Untangling individual response profiles revealed strong infiltration with L AG3+ and PD-L1+ immune cells when treatments failed, but almost complete exclusion of checkpointexpressing lymphocytes in long-term survivors. Conclusions: By applying two tumor cell lysates we demonstrate that neoantigen quality outranks quantity. This should be considered prior to designing cancer vaccine-based combination approaches. Keywords: Tumor lysate, Mutational load, MMR deficiency, In vivo imaging, Primary cell lines
*Correspondence: [email protected]‑rostock.de † Inken Salewski and Yvonne Saara Gladbach contributed equally to this work 1 Department of Medicine, Clinic III‑Hematology, Oncology, Palliative Care, Rostock University Medical Center, Ernst‑Heydemann‑Str. 6, 18057 Rostock, Germany Full list of author information is available at the end of the article
Background The idea of using whole tumor lysates as vaccines dates back to the late 1970ies and aims at the induction of a vigorous immune response against cancer [1]. Highly immunogenic tumor-derived neo-epitopes must be present to be recognized by cytotoxic T cells. Antigen (Ag)loaded dendrit
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