Abstract 2111: Mobilization of memory natural killer cells in cancer immunotherapy
Authors: Medina-Luna Daniel , Gamage Gayani , Scur Michal , Zein Haggah , Parsons Brendon , Makrigiannis Andrew P. 
Published: June 2022

Introduction: Immunological memory has long been exclusively attributed to T and B lymphocytes; however, we now know that natural killer (NK) cells also possess an analogous function. Studies of Rag-1-deficient mice (Rag1-/-), which lack T and B cells, provided evidence of NK cell-mediated immunological memory. As NK cells also possess a natural capacity to eliminate tumor cells, we set out to define the role of NK cell memory in anti-cancer immune responses using NK cell-targeted cancer immunotherapy through immunization.

Methods: Rag1-/- mice (n=15) were immunized with the E749-57 RAHNIVYTIF (R9F) peptide from Human Papillomavirus 16, using the proprietary DepoVax (DPX) vaccine formulation, (IMV, Inc., NS Canada). Age-matched Rag1-/- mice (n=15) treated with the DPX vehicle alone served as controls. Sixteen days after immunization, all mice were flank-injected with C3 tumor cells, which express the R9F antigen. Tumor appearance and tumor growth rates were recorded. To test the requirement for Perforin, Rag1/Prf1/- mice (n=15) or age-matched Rag1-/- (n=15) were similarly immunized and tumor challenge. To determine the antigen specificity of NK cell memory, Rag1-/- mice (n=15) were immunized with the chicken-ovalbumin model antigen OVA257-265 SIINFEKL (DPX-SIINFEKL) or DPX vehicle (n=15). Mice for these experiments were implanted with C3 cells that express the ovalbumin gene and present the SIINFEKL antigen (C3-OVA cells). For all groups, tumor appearance and tumor growth rates were recorded.

Results: Rag1-/- mice vaccinated with DPX-R9F had better protection against C3 tumor development, with 60% remaining tumor-free in comparison to the DPX vehicle control cohort, in which all mice developed tumors. Additionally, the tumor growth rate in DPX-R9F immunized mice was significantly slower than in the control cohort. Perforin has a key role in mediating the observed anti-tumor responses as Rag1/Prf1/- mice vaccinated with DPX-R9F had less tumor protection compared to the Rag1-/- mice, of which only 20% remained tumor-free. Finally, we found 60% of mice immunized with DPX-SIINFEKL and challenged with C3-OVA remained tumor-free, indicating that tumor protection could be induced by distinct antigens.

Conclusions: Our preliminary results suggest that DPX-R9F or DPX-SIINFEKL immunization induces antigen-specific protection against tumor development in mice in a T cell- and B cell-independent manner. These immunizations appear to induce memory NK cells to mount antigen-specific antitumor responses that rely on Perforin as an effector molecule. By demonstrating that memory NK cells have a role in protection against tumor development, future cancer immunotherapies could be improved by priming not only T cells but also NK cells, proposing a therapeutic approach with better patient outcomes and improving, at the same time, the safety profile of these immunotherapies.

Citation Format: Daniel Medina-Luna, Gayani Gamage, Michal Scur, Haggah Zein, Brendon Parsons, Andrew P. Makrigiannis. Mobilization of memory natural killer cells in cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2111.