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343 Oncolytic viruses induce sustained anti-tumor cytotoxicity in NK cells
  1. Xin Ru Jiang1,2,
  2. Hind Rafei1,
  3. Rafet Basar1,
  4. May Daher1,
  5. Qingnan Liang1,
  6. Inci Biederstadt1,
  7. Patrick Zhang1,
  8. Donghai Xiong1,
  9. Jiajinlong Kang1,2,
  10. Joy Gumin1,
  11. Mayra Shanley1,
  12. Corry Jones1,
  13. April Gilbert1,
  14. Hila Shaim1,
  15. Luis Muniz-Feliciano1,
  16. Gary Deyter1,
  17. Pinaki Banerjee1,
  18. Madison Moore2,
  19. Ye Li1,
  20. Dexing Fang1,
  21. Sunil Acahrya1,
  22. Hong Jiang1,
  23. Nadima Uprety1,
  24. Rejeena Shrestha1,
  25. Byron Jia1,
  26. Paul Daniel1,
  27. Maliha Munir1,2,
  28. Oluwatosin Banjo1,
  29. Elizabeth J Shpall1,
  30. Abhinav Jain1,
  31. Ken Chen1,
  32. Frederick Lang1,
  33. Candelaria Gomez Manzano1,
  34. Juan Fueyo1 and
  35. Katy Rezvani1
  1. 1The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  2. 2The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.

Abstract

Background Natural killer (NK) cells are crucial for eliminating tumor and virally-infected cells by integrating signals from activating and inhibitory receptors. While NK-cell therapy has shown success in treating leukemias and lymphomas, its effectiveness against solid tumors remains limited due to tumor-mediated suppression. Oncolytic viruses, which selectively target and kill tumor cells while enhancing antitumor immunity, offer a promising approach to overcoming this suppression. Our study aims to elucidate the mechanisms behind oncolytic adenovirus-mediated activation of NK cells, thereby laying the groundwork for the clinical translation of this combination therapy for solid tumors.

Methods We conducted a series of in vitro and in vivo experiments to evaluate the additive cytotoxic effects of NK cells and oncolytic viruses on pancreatic ductal adenocarcinoma (PDAC) and glioblastoma. In vitro, tumor cells were infected with the oncolytic adenovirus delta24RGD and subsequently co-cultured with NK cells. Phenotypic changes were analyzed using CyTOF, while cytotoxicity was assessed using xCelligence and Incucyte. For long-term cytotoxicity assays, NK cells were purified from the co-culture and subjected to multiple tumor rechallenges to test their sustained cytotoxic potential. In vivo, we utilized a patient-derived xenograft glioblastoma mouse model to assess the therapeutic efficacy of the combination treatment, closely monitoring tumor growth and survival.

Results NK cells and oncolytic viruses exhibited an additive cytotoxicity effect against both PDAC tumors (figure 1A) and glioblastoma (figure 1B). Phenotypic analysis revealed that NK cells exposed to infected tumors for 96 hours exhibited a hyperactivated phenotype characterized by increased expression of activating receptors such as NKG2D, CD25, and CD69, as well as cytotoxic markers including TRAIL and CD107a (figure 1C, D). In vivo studies further validated these findings, demonstrating superior efficacy of the combination therapy against glioblastoma. The combination of NK cells and oncolytic virus significantly prolonged survival in a glioblastoma mouse model compared to monotherapy (figure 1E-G). Activation of NK cells by virally infected tumors were shown to require direct cell-to-cell contact (figure 2A, B), likely facilitated by the oncolytic virus-mediated modulation of NK cell ligand expression on tumor cells (figure 2C, D). Importantly, the hyperactivation of NK cells induced by infected tumors resulted in sustained cytotoxicity over multiple rounds of tumor rechallenge (figure 2E, F).

Conclusions Oncolytic viruses significantly enhance the long-term antitumor efficacy of NK cells, highlighting their therapeutic potential against aggressive solid tumors. This combinatorial approach holds promise for enhancing the effectiveness of NK cell-based immunotherapies in clinical settings.

Abstract 343 Figure 1

NK cells exhibit enhanced cytotoxicity against oncolytic adenovirus-infected tumor cells

Abstract 343 Figure 2

NK cell activation by virally infected tumor cells requires cell-to-cell contact, and induces NK long-term cytotoxicity

http://creativecommons.org/licenses/by-nc/4.0/

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